Xanthine derivatives as selective hm74a agonists

ABSTRACT

The present invention relates to compounds of formula (I) which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing these active compounds and the use of the compounds in therapy, for example, in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial

The present invention relates to compounds which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing these compounds and the use of the compounds in therapy, for example, in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.

Dyslipidaemia is a general term used to describe individuals with aberrant lipoprotein profiles. Clinically, the main classes of compounds used for the treatment of patients with dyslipidaemia, and therefore at risk of cardiovascular disease are the statins, fibrates, bile-acid binding resins and nicotinic acid. Nicotinic acid (Niacin, a B vitamin) has been used clinically for over 40 years in patients with various forms of dyslipidaemia. The primary mode of action of nicotinic acid is via inhibition of hormone-sensitive triglyceride lipase (HSL), which results in a lowering of plasma non-esterified fatty acids (NEFA) which in turn alters hepatic fat metabolism to reduce the output of LDL and VLDL (low and very low density lipoprotein). Reduced VLDL levels are thought to lower cholesterol ester transfer protein (CETP) activity to result in increased HDL (high density lipoprotein) levels which may be the cause of the observed cardiovascular benefits. Thus, nicotinic acid produces a very desirable alteration in lipoprotein profiles; reducing levels of VLDL and LDL whilst increasing HDL. Nicotinic acid has also been demonstrated to have disease modifying benefits, reducing the progression and increasing the regression of atherosclerotic lesions and reducing the number of cardiovascular events in several trials.

The observed inhibition of HSL by nicotinic acid treatment is mediated by a decrease in cellular cyclic adenosine monophosphate (cAMP) caused by the G-protein-mediated inhibition of adenylyl cyclase. Recently, the G-protein coupled receptors HM74 and HM74A have been identified as receptors for nicotinic acid (PCT patent application WO02/84298; Wise et. al. J Biol. Chem., 2003, 278 (11), 9869-9874). The DNA sequence of human HM74A may be found in Genbank; accession number AY148884. Two further papers support this discovery, (Tunaru et. al. Nature Medicine, 2003, 9(3), 352-255 and Soga et. al. Biochem Biophys Res Commun., 2003, 303 (1) 364-369), however the nomenclature differs slightly. In the Tunaru paper what they term human HM74 we term HM74A and in the Soga paper HM74b is identical to HM74A. Cells transfected to express HM74A and/or HM74 gain the ability to elicit G_(i) G-protein mediated responses following exposure to nicotinic acid. In mice lacking the homologue of HM74A (m-PUMA-G) nicotinic acid fails to reduce plasma NEFA levels.

Certain xanthine derivatives have been synthesised and disclosed in the prior art. For example, EP0389282 discloses xanthine derivatives as potential mediators of cerebrovascular disorders. A range of xanthine derivatives were identified as adenosine receptor antagonists by Jacobson et. al. in J. Med. Chem., 1993, 36, 2639-2644.

We now present a group of xanthine derivatives which are selective agonists of the nicotinic acid receptor HM74A and are thus of potential benefit in the treatment, prophylaxis and suppression of diseases where under-activation of this receptor either contributes to the disease or where activation of the receptor will be beneficial.

SUMMARY OF THE INVENTION

The present invention provides xanthine derivatives and the use of these derivatives in therapy, for example, in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial. For example, in treatment of diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia. As such, the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as the cardiovascular indications associated with type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. The compounds may also be of use in the treatment of inflammatory diseases or conditions, as set out further below.

Intermediates, formulations, methods and processes described herein form further embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of this invention we provide at least one chemical entity selected from compounds of formula (I)

-   -   and pharmaceutically acceptable derivatives thereof, wherein     -   R¹ represents -(alkylene)_(m)-X-(alkylene)_(n)-Y;     -   Wherein X represents A, A1, A2 or a direct link;

A represents a group selected from

-   -   cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl,         and —CH₂—OC(O)—;     -   A1 represents a group selected from     -   —CH₂—O—(CH₂)_(q)aryl-O—, —CH₂—O—(CH₂)_(w)N(R⁵)C(O)O—,         —CH₂—N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)—,         —CH₂—(O)_(p)—(CH₂)_(q)C(O)NR⁵—, —CH₂—N(R⁵)C(O)N(R⁵)—,         —CH₂—C(O)N((CH₂)_(w)OH)—, —CH₂—NR⁵—S(O)₂—, CH₂—S(O)₂NR⁵—,         —CH₂—C(O)O—, —O—, —NR⁵—, and —S—;     -   A2 represents —CH(OH)—;     -   When X is A, A1 or A2, Y represents a group selected from     -   heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl,         —NH-aryl, —O(CH₂)_(n)-aryl, —O-heteroaryl, —OR⁵, —C(O)OR⁵,         —C(O)O—C₆aryl, —OC(O)R⁴, —CH(aryl)₂, —CH(heteroaryl)₂, and —C₁₋₆         haloalkyl;     -   When X is A1 and Y is selected from     -   —O(CH₂)_(n)-aryl, —O-heteroaryl, —OR⁵, —OC(O)R⁴, and —NH-aryl,     -   n is an integer selected from 2, 3, 4 and 5;     -   When X is A1 and Y is —C₁₋₆ haloalkyl, or when X is A2, n is an         integer selected from 1, 2, 3, 4 and 5;     -   When X is a direct link, (m+n) is an integer selected from 2 to         10;     -   When X is a direct link and (m+n) is an integer selected from 3         to 10, Y represents a group selected from     -   —C(O)(CH₂)_(q)OR⁴, —C(O)-aryl, —C(O)-heteroaryl,         —C(O)-heterocyclyl, heteroaryl, heterocyclyl, Aryl, 3 or 4 ring         fused system, —CH(aryl)₂, —CH(heteroaryl)₂, —OR⁵, —NR⁵R⁶,         —NR⁵C(O)OR⁷, —(O)_(p)C(O)NR⁵R⁷, and —NR⁵C(O)R⁷;     -   When X is a direct link and (m+n) is 2, Y represents a group         selected from —OR⁵, —NH₂, and —NR⁵C(O)OR⁸;     -   When Y incorporates a ring, that ring may be optionally         substituted by one or more of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆         alkynyl, halogen, —(CH₂)_(q)NR⁵R⁷,         —(CH₂)_(q)—(O)_(p)—(CH₂)_(q)—N(R⁵)C(O)OR⁸,         —(CH₂)_(q)—N(R⁵)C(O)R⁸, —(CH₂)_(q)—(O)_(p)—(CH₂)_(q)—C(O)NR⁵R⁶,         —(CH₂)_(q)—N(R⁵)C(O)N(R⁵)R⁶, (CH₂)_(q)—C(O)N((CH₂)_(m)OH)R⁵,         —(CH₂)_(q)—N(R⁵)—S(O)₂R⁸, —CH₂—S(O)₂N(R⁵)R⁶, —C₁₋₆ haloalkyl,         —OCF₃, —OCH(F)₂, —OCH₂F, —C(O)OR⁵, —OR⁵, —R⁸CN, —CN, —SO₂R⁹,         —(CH₂)_(n)heteroaryl, —(CH₂)_(n)heterocycyl,         —(CH₂)_(n)cycloalkyl, —(CH₂)_(n)cycloalkenyl, and         —(CH₂)_(n)aryl;

Provided that when X is A1, A1 is —O— and Y is a ring which is substituted by aryl or heteroaryl, then m is an integer selected from 3, 4 and 5;

R² is selected from hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of a group independently selected from: C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁₋₆ haloalkyl, halogen, —CN, —OR⁴, —(CH₂)_(n)COR⁴, —C(O)OR⁴, —OCOR⁴, —(CH₂)_(n)NR⁵R⁶, —(NH)_(p)CONR⁵R⁶, —OCONR⁵R⁷, and —NR⁵C(O)OR⁷;

-   -   R³ represents a group selected from halogen and CN;     -   R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆         alkynyl, —(CH₂)_(n)cycloalkyl, —(CH₂)_(n) cycloalkenyl,         —(CH₂)_(n) heterocyclyl, —(CH₂)_(n) aryl, and —(CH₂)_(n)         heteroaryl;     -   R⁵ and R⁶ are independently selected from hydrogen and C₁₋₄         alkyl;     -   R⁷ represents a group selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,         C₂₋₆ alkynyl, —(CH₂)_(t) cycloalkyl, —(CH₂)_(n) cycloalkenyl,         —(CH₂)_(t) heterocyclyl, —(CH₂)_(t) aryl, and —(CH₂)_(t)         heteroaryl;     -   R⁸ represents a group selected from C₁₋₄ alkyl;     -   R⁹ represents a group selected from C₁₋₆ alkyl C₂₋₆ alkenyl,         C₂₋₆ alkynyl, —(CH₂)_(n) cycloalkyl, —(CH₂)_(n)cycloalkenyl,         —(CH₂)_(n)heterocyclyl, —(CH₂)_(n) aryl, —(CH₂)_(n)heteroaryl,         and CN;     -   m represents an integer selected from 1, 2, 3, 4 and 5;     -   n represents an integer selected from 0, 1, 2, 3, 4 and 5;     -   p represents an integer selected from 0 and 1;     -   q represents an integer selected from 0, 1 and 2;     -   t represents an integer selected from 1 and 2; and     -   w represents an integer selected from 2, 3 and 4.

The compounds are of use in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial. For example in treatment of diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia. As such, the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as the cardiovascular indications associated with type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such the compounds of the present invention may find use as agonists or partial agonists of HM74A.

According to another aspect of this invention we provide at least one chemical entity selected from compounds of formula (I)

and pharmaceutically acceptable derivatives thereof, wherein R¹ represents -(alkylene)_(m)-X-(alkylene)_(n)-Y Wherein X represents A, A1, A2 or a direct link;

A represents a group selected from;

cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, and —CH₂—OC(O)—;

A1 represents a group selected from:

—CH₂—O—(CH₂)_(q)aryl-O—, —CH₂—O—(CH₂)_(w)N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)—, —CH₂—(O)_(p)—(CH₂)_(q)C(O)NR⁵—, —CH₂—N(R⁵)C(O)N(R⁵)—, —CH₂—C(O)N((CH₂)_(m)OH)—, —CH₂—NR⁵—S(O)₂—, CH₂—S(O)₂NR⁵—, —CH₂—C(O)O—, —O—, —NH—, and —S—;

A2 represents:

—CH(OH)—;

When X is A, A1 or A2, Y represents a group selected from:

heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, —NH-aryl, —O(CH₂)_(n)-aryl, —O-heteroaryl, —OR⁵, —C(O)OR⁵, —C(O)O—C₆ aryl, —OC(O)R⁵, —CH(aryl)₂, —CH(heteroaryl)₂, and —C₁₋₆ haloalkyl;

When X is A1 and Y is selected from:

—O(CH₂)_(n)-aryl, —O-heteroaryl, —OR⁵, —OC(O)R⁵, and —NH-aryl, n is an integer selected from 2, 3, 4 and 5;

When X is A1 and Y is —CF₃, or when X is A2, n is an integer selected from 1, 2, 3, 4 and 5;

When X is a direct link, (m+n) is an integer selected from 2 to 10;

When X is a direct link and (m+n) is an integer selected from 3 to 10, Y represents a group selected from: —C(O)(CH₂)_(q)OR⁵, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocyclyl, heteroaryl, heterocyclyl, Aryl, 3 or 4 ring fused system, —CH(aryl)₂, —CH(heteroaryl)₂, —OR⁵, —NR⁵R⁶, —NC(O)OR⁸, —(O)_(p)C(O)NR⁵R⁶, and —NR⁵C(O)R⁸;

When X is a direct link and (m+n) is 2, Y represents a group selected from: —OR⁵, —NH₂, and —NC(O)OR⁸;

When Y incorporates a ring, that ring may be optionally substituted by one or more of: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, —NH₂, —(CH₂)_(q)—(O)_(p)—(CH₂)_(p)—N(R⁵)C(O)OR⁸, —(CH₂)_(p)—N(R⁵)C(O)R⁸, —(CH₂)_(q)—(O)_(p)—(CH₂)_(p)—C(O)NR⁵R⁶, —(CH₂)_(p)—N(R⁵)C(O)N(R⁵)R⁶, —(CH₂)_(p)—C(O)N((CH₂)_(m)OH)R⁵, —(CH₂)_(p)—N(R⁵)—S(O)₂R⁸, —CH₂—S(O)₂N(R⁵)R⁶, —C₁₋₆ haloalkyl, —OCF₃, —OCH(F)₂, —OCH₂F, —C(O)OR⁵, —OR⁵, —(R⁸)_(p)CN, —SO₂R⁹, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)heterocycyl, —(CH₂)_(n)cycloalkyl, —(CH₂)_(n)cycloalkenyl, and —(CH₂)_(n)aryl;

Provided that when X is A1, A1 is —O— and Y is a ring which is substituted by aryl or heteroaryl, then m is an integer selected from 3, 4 and 5;

R² is selected from: H; or C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, cycloalkenyl heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁₋₆ haloalkyl, halogen, —CN, —OR⁴, —(CH₂)_(n)COR⁴, —C(O)OR⁴, —OCOR⁴, —(CH₂)_(n)NR⁵R⁶, —(NH)_(p)CONR⁵R⁶, —OCONR⁵R⁷, and —NHC(O)OR⁷; R³ is selected from: halogen and CN; R⁴ is selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂), cycloalkyl, —(CH₂)_(r), cycloalkenyl, —(CH₂)_(n)heterocyclyl, —(CH₂)_(n) aryl, and —(CH₂)_(n)heteroaryl; R⁵ and R⁶ are selected from: hydrogen and C₁₋₄ alkyl;

R⁷ is selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(t) cycloalkyl, —(CH₂)_(n)cycloalkenyl, —(CH₂)_(t) heterocyclyl, —(CH₂)_(t) aryl, and —(CH₂)_(t) heteroaryl;

R⁸ is selected from C₁₋₄ alkyl; R⁹ is selected from, C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n) cycloalkyl, —(CH₂)_(n)cycloalkenyl, —(CH₂)_(n)heterocyclyl, —(CH₂)_(n) aryl, and —(CH₂)_(n)heteroaryl, CN; m represents an integer selected from: 1, 2, 3, 4 and 5; n represents an integer selected from: 0, 1, 2, 3, 4 and 5; p represents an integer selected from: 0 and 1; q represents an integer selected from: 0, 1 and 2; t represents an integer selected from: 1 and 2; w represents an integer selected from: 2, 3 and 4.

In one embodiment, X represents A or A1. In a further embodiment, A is selected from heteroaryl, heterocyclyl, and A1 is selected from CH₂—O—(CH₂)_(w)N(R⁵)C(O)O—, for example CH₂—O—(CH₂)₂NHC(O)O—, CH₂—N(R⁵)C(O)O— for example CH₂—NHC(O)O, CH₂—N(R⁵)C(O)— for example, CH₂—NHC(O)—, CH₂—(O)_(p)—(CH₂)_(q)C(O)NR⁵— for example CH₂C(O)NCH₃—, CH₂—N(R⁵)C(O)N(R⁵)— for example CH₂—NHC(O)NCH₃—, CH₂—C(O)N((CH₂)_(m)OH)— for example CH₂—C(O)N((CH₂)₂OH)—, CH₂—NR⁵—S(O)₂— for example CH₂—NH—S(O)₂—, C₁₋₁₂—S(O)₂NR⁵— for example CH₂—S(O)₂NCH₃—, and CH₂—C(O)O—. In another embodiment, X represents A and A represents a heteroaryl. In another embodiment A represents a heteroaryl comprising a nitrogen heteroatom, for example, triazolyl, furazanyl, oxadiazolyl, tetrazolyl, imidazolyl or pyrazolyl.

In one embodiment, Y represents an optionally substituted group selected from: aryl, for example phenyl or napthyl, heteroaryl, for example pyridinyl, thiazolyl, thienyl, benzofuranyl or indolyl, and O-aryl, for example O-phenyl.

In a further embodiment, Y is substituted by one or more groups selected from OR⁵ for example OH or OCH₃, halogen, for example F or Cl, aryl, for example phenyl, C₁₋₆ haloalkyl for example CF₃ or CH₂CF₃, OCF₃, (R⁸)_(P)CN for example CN, (CH₂)_(p)—N(R⁵)—S(O)₂R⁸, for example NHSO₂CH₃ and SO₂R⁹, for example SO₂CH₃.

In yet a further embodiment Y is substituted by one or more groups selected from OR⁵, halogen, C₁₋₆ haloalkyl, and —(CH₂)_(q)—N(R⁵)C(O)R⁸.

In another embodiment, Y is substituted by one or more groups selected from halogen, and C₁₋₄ haloalkyl.

In yet a further embodiment, wherein Y is a ring, it is not further substituted.

In one embodiment of the invention, when X represents A or A1, and A represents cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl, and A1 represents —CH₂—O—(CH₂)_(w)N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)—, —CH₂—(O)_(p)—(CH₂)_(q)C(O)NR⁵—, —CH₂—N(R⁵)C(O)N(R⁵)—, or —CH₂—C(O)N((CH₂)_(m)OH)—, and Y represents a ring, for example when X represents oxadizolyl, tetrazolyl or pyrazolyl and Y represents phenyl, pyridinyl, or thienyl, m is an integer selected from 3 and 4 and n is an integer selected from 0 and 1, for example m is 4 and n is 0, or m is 3 and n is 1;

In one embodiment R² represents C₁₋₁₀ alkyl which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁₋₆ haloalkyl, halogen, —CN, —OR⁴, —(CH₂)_(n)COR⁵, —C(O)OR⁴, —OCOR⁴, —(CH₂)_(n)NR⁵R⁵, and —(NH)_(p)CONR⁵R⁶. In a further embodiment, R² is selected from C₁₋₁₀ alkyl which may be optionally substituted by one or more of: cycloalkyl, aryl, heteroaryl, C₁₋₆ haloalkyl, halogen, —CN, —OR⁴, —(CH₂)_(n)COR⁵, —C(O)OR⁴ and —OCOR⁴. In yet a further embodiment R² is selected from C₁₋₆ alkyl which may be optionally substituted by one or more of: cycloalkyl, C₁₋₆ haloalkyl, halogen, —CN or —OR⁴. In yet another further embodiment, R² is selected from C₃₋₆ alkyl, for example butyl or pentyl.

In one embodiment, R³ represents halogen. In a further embodiment, R³ is selected from: chlorine and bromine. In another embodiment, R³ represents chlorine.

With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atom and may occur as recemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

Where a compound of formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compound of the invention and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.

Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or HPLC of a stereoisomeric mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included in the present invention. One form may have an advantage over another form, for example one form may have improved stability over another form.

It is to be understood that the present invention includes any combination of particular embodiments and covers all combinations of particular substituents described hereinabove.

Throughout the present specification and the accompanying claims the words “comprise” and “include” and variations such as “comprises”, “comprising”, “includes” and “including” are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows.

As used herein, the term “alkyl” (when used as a group or as part of a group) refers to a straight or branched hydrocarbon chain unless specified otherwise, containing the specified number of carbon atoms. For example, C₃-C₁₀alkyl means a straight or branched hydrocarbon chain containing at least 3 and at most 10 carbon atoms. Examples of alkyl as used herein include, but are not limited to methyl (Me), ethyl (Et), n-propyl and i-propyl.

The term “alkylene” or as used herein means both straight and branched chain, or cyclic saturated hydrocarbon linker groups. Examples of alkylene groups include methylene (—CH₂—), ethylene (—CH₂CH₂—), ethene (—CH═CH—), or cyclopropylene and the like. For example, as used herein, -(alk)_(n)-, where n is 3 represents —(CH₂)₃—, —C(CH₃)₂—, —CH₂CH═CH—, or -cyclopropylene- and the like. For example as used herein, -(alk)_(m)- where m is 4 represents —(CH₂)₄—, —CH₂C(CH₃)₂—, —CH₂CH═CHCH₂—, or —CH₂cyclopropylene- and the like.

The term “alkenyl” as used herein refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms which contains one or more double bonds.

The term “alkynyl” as used herein refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms which contains one or more triple bonds.

The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.

The term “cycloalkylene” as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon linker groups. Examples of such groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene and the like.

The term “cycloalkenyl” as used herein refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms containing one or more carbon-carbon double bonds. Examples of such groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.

The term “cycloalkenylene” as used herein refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon linker groups containing one or more carbon-carbon double bonds. Examples of such groups include cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene or cyclooctenylene and the like.

The term “aryl” as used herein refers to a C₆₋₁₂ monocyclic, bicyclic or tricyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like.

The term “heteroaryl” as used herein refers to a 5-6 membered monocyclic aromatic ring or a fused 8-10 membered bicyclic aromatic ring, containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur. There may be one or more optional oxo substituents on the ring carbon atoms. Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like. Examples of such fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.

The term “heterocyclyl” as used herein refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur. There may be one or more optional oxo substituents on the ring carbon atoms. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like. Examples of such bicyclic rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl and the like.

The term “3 or 4 ring fused system” as used herein refers to a fused 12-18 membered tricyclic or tetracyclic ring which contains 1 to 4 heteroatoms of N and wherein at least one ring is aromatic. There may be one or more optional oxo substituents on the ring carbon atoms. Examples of such fused aromatic rings include carbazolyl, acenaphthyl, naphthotriazolyl and the like.

The terms “halogen” or “halo” as used herein refer to a fluorine, chlorine, bromine or iodine atom.

The term “C₁₋₆ haloalkyl” as used herein refers to a C₁₋₆ alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.

As used herein, where a group is referred to as being “substituted” by another group or having “one or more substituents” unless a particular position for such a substitution is specified it is to be understood that a substitution may be present at any position in the group.

The term “pharmaceutically acceptable derivative” as used herein refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, salts, solvates or esters, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice, which is incorporated herein by reference.

As used herein, the term “pharmaceutically acceptable” used in relation to an ingredient (active ingredient, diluent, excipient or carrier) which may be included in a pharmaceutical formulation for administration to a patient, refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.

As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a pharmaceutically acceptable derivative thereof) and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. The solvent used may be a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. An example of a solvent that may be used is water, in which case the solvate may be referred to as a hydrate of the solute in question.

It will be appreciated that, for pharmaceutical use, the “salt or solvate” referred to above will be a pharmaceutically acceptable salt or solvate. However, other salts or solvates may find use, for example, in the preparation of a compound of formula (I) or in the preparation of a pharmaceutically acceptable salt or solvate thereof.

Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Suitable pharmaceutically acceptable salts include alkali metal salts formed from the addition of alkali metal bases such as alkali metal hydroxides. Examples of suitable alkali metal salts include sodium salts and potassium salts. Other suitable pharmaceutically acceptable salts include alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts; or salts with organic bases such as ethanolamine, triethanolamine, ethylene diamine, triethylmine, choline and meglumine; or salts with amino acids such as arginine, lysine and histidine.

Esters may be active in their own right and/or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. An ester may be formed at a carboxylic acid (—C(O)OH) group, by methods well known in the art involving reaction with the corresponding alcohol. For example, esters may be C₁₋₆alkyl esters, e.g. methyl esters, ethyl esters, and the like.

As used herein, the term “compounds of the invention” means the compounds according to Formula I and the pharmaceutically acceptable derivatives thereof. The term “a compound of the invention” means any one of the compounds of the invention as defined above.

As used herein the term “at least one chemical entity” means at least one chemical substance chosen from the group of compounds consisting of compounds of formula I and pharmaceutically acceptable derivatives thereof.

In one aspect of the invention there is provided substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 1. In another aspect of the invention there is provided substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 2.

Thermal analysis on samples of substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione forms 1 and 2 was carried out. Thus, there is provided substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (form 1 or form 2) having a melting point onset measured by DSC (±0.5° C.) of: 160° C. or greater and 147° C. or greater, respectively.

Samples of substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 1, and 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 2, prepared as described hereinafter, gave the X-ray powder diffraction patterns of FIGS. 1-2. The X-ray diffraction pattern is unique to the crystalline form. The substantially crystalline forms exhibit diffraction patterns with a unique set of diffraction peaks which can be expressed in 2 theta angles (°).

2 Theta diffraction anglet account for positions of various peaks in the X-ray diffraction pattern. Slight variations in observed 2 theta angles are expected based on the specific diffractometer employed and the analyst's sample preparation technique.

The substantially crystalline forms of 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione can be identified by the presence of a characteristic 2 theta angle peak, or by multiple 2 theta angles which are reasonably characteristic of the particular crystalline forms. To identify substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (form 1), these peaks occur at the following positions, expressed in 2 theta angles (±0.1 degrees): 5.4, 6.7, 9.7, 11.1, 12.9, 14.0, 15.6, 16.3, 16.7, 23.1 degrees. To identify substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (form 2), these peaks occur at the following positions, expressed in 2 theta angles (±0.1 degrees): 5.2, 6.6, 10.4, 11.2, 13.4, 15.6, 18.1, 19.5, 20.9 degrees. In one embodiment at least one of the foregoing 2 theta angles are employed to identify substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 1 and substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 2. In other embodiments at least 2, 3, 4 or 5 (where applicable) of the foregoing 2 theta angles are employed to identify substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 1, substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 2.

Some margin of error is present in each of the 2 theta angle assignments. The margin of error in the foregoing 2 theta angles is approximately ±0.1 degrees for each of the foregoing peak assignments.

Since some margin of error is possible in the assignment of 2 theta angles, the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form. For example, one skilled in the art can overlay an X-ray powder diffraction pattern of an unidentified form of 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione, obtained using the methods described herein, see FIG. 3 for example, and readily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same as the X-ray powder diffraction pattern of substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione Form 1 or 2. If the X-ray powder diffraction pattern is substantially the same as that shown in any of FIGS. 1-2, the previously form can be readily and accurately identified.

As used herein, the term “substantially crystalline form” means that it is substantially free of amorphous form 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione. By “substantially free” is meant containing less than 50% of the amorphous form, in one aspect less than 20% of the amorphous form, in another aspect less than 10% of the amorphous form, in another aspect less than 5% of the amorphous form, in another aspect less than 2% of the amorphous form, in another aspect less than 1% of the amorphous form.

The present invention provides a method for the preparation of substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form as described herein.

Compounds of formula (I) are of potential therapeutic benefit in the treatment and amelioration of the symptoms of many diseases of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such, the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke.

It has been reported that the HM74 and HM74A receptors are involved in inflammation (WO02084298). Inflammation represents a group of vascular, cellular and neurological responses to trauma. Inflammation can be characterised as the movement of inflammatory cells such as monocytes, neutrophils and granulocytes into the tissues. This is usually associated with reduced endothelial barrier function and oedema into the tissues. Inflammation with regards to disease typically is referred to as chronic inflammation. Such chronic inflammation may manifest itself through disease symptoms. The aim of anti-inflammatory therapy is therefore to reduce this chronic inflammation and allow for the physiological process of healing and tissue repair to progress.

Examples of inflammatory diseases or conditions for which the compounds of the present invention may demonstrate utility include those of the joint, for example arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, the enteropathy provoked by non-steroidal anti-inflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of the pancreas, (e.g. inflammation associated with diabetes melitus and complications thereof, of the kidney (e.g. glomerulonephritis), of the skin (e.g. dermatitis, psoriasis, eczema, urticaria, burn injury), of the eye (e.g. glaucoma) as well as of transplanted organs (e.g. rejection) and multi-organ diseases (e.g. systemic lupus erythematosis, sepsis) and inflammatory sequelae of viral or bacterial infections and inflammatory conditions associated with atherosclerosis and following hypoxic or ischaemic insults (with or without reperfusion), for example in the brain or in ischaemic heart disease.

In one embodiment, the compounds of this invention are useful in the treatment and prevention of inflammation, diabetes and cardiovascular diseases or conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.

Nicotinic acid has a significant side effect profile, possibly because it is dosed at high level (gram quantities daily). The most common side effect is an intense cutaneous flushing. In certain embodiments of the present invention the compounds may exhibit reduced side effects compared to nicotinic acid. HM74A has been identified as a high affinity receptor for nicotinic acid whilst HM74 is a lower affinity receptor. The compounds of the present invention show greater affinity for HM74A than for HM74 therefore may find use as selective HM74A agonists or partial agonists.

The potential for compounds of formula (I) to activate HM74A may be demonstrated, for example, using the following in vitro whole cell assays:

In-Vitro Testing

For transient transfections, HEK293T cells (HEK293 cells stably expressing the SV40 large T-antigen) were maintained in DMEM containing 10% foetal calf serum and 2 mM glutamine. Cells were seeded in 90 mm culture dishes and grown to 60-80% confluence (18-24 h) prior to transfection. Human HM74A (GenBank™ accession number AY148884) was subcloned in to a mammalian expression vector (pcDNA3; Invitrogen) and transfected using Lipofectamine reagent. For transfection, 9 μg of DNA was mixed with 30 μl Lipofectamine in 0.6 ml of Opti-MEM (Life Technologies Inc.) and was incubated at room temperature for 30 min prior to the addition of 1.6 ml of Opti-MEM. Cells were exposed to the Lipofectamine/DNA mixture for 5 h and 6 ml of 20% (v/v) foetal calf serum in DMEM was then added. Cells were harvested 48 h after transfection. Pertussis toxin treatment was carried out by supplementation into media at 50 ngml⁻¹ for 16 h. All transient transfection studies involved co-transfection of receptor together with the G_(i/o) G protein, G_(o1)α.

For generation of stable cell lines the above method was used to transfect CHO-K1 cells seeded in six well dishes grown to 30% confluence. These cells were maintained in DMEM F-12 HAM media containing 10% foetal calf serum and 2 mM glutamine. 48 h post-transfection the media was supplemented with 400 μg/ml Geneticin (G418, Gibco) for selection of antibiotic resistant cells. Clonal CHO-K1 cell lines stably expressing HM74A were confirmed by [³⁵S]-GTPγS binding measurements, following the addition of nicotinic acid.

P2 membrane preparation—Plasma membrane-containing P2 particulate fractions were prepared from cell pastes frozen at −80° C. after harvest. All procedures were carried out at 4° C. Cell pellets were resuspended in 1 ml of 10 mM Tris-HCl and 0.1 mM EDTA, pH 7.5 (buffer A) and by homogenisation for 20 s with a Ultra Turrax followed by passage (5 times) through a 25-gauge needle. Cell lysates were centrifuged at 1,000 g for 10 min in a microcentrifuge to pellet the nuclei and unbroken cells and P2 particulate fractions were recovered by microcentrifugation at 16,000 g for 30 min. P2 particulate fractions were resuspended in buffer A and stored at −80° C. until required.

[³⁵S]-GTPγS binding—assays were performed at room temperature in 384-well format based on methods described previously, (Wieland, T. and Jakobs, K. H. (1994) Methods Enzymol. 237, 3-13). Briefly, the dilution of standard or test compounds were prepared and added to a 384-well plate in a volume of 10 μl. Membranes (HM74A or HM74) were diluted in assay buffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl₂, pH7.4) supplemented with saponin (60 μg/ml), Leadseeker WGA beads (Amersham; 250 μg/well) and 10 μM GDP, so that the 20 μl volume added to each well contains 5 μg of membranes. [³⁵S]-GTPγS (1170 Ci/mmol, Amersham) was diluted (1:1500) in assay buffer and 20 μl added to each well. Following the addition of the radioligand, the plates were sealed, pulse spun and incubated for 4 hours at room temperature. At the end of the incubation period the plates were read on a Leadseeker machine (VIEWLUX PLUS; Perkin-Elmer) to determine the levels of specific binding.

These assays were refined by reducing the final assay volume to 10 μl. For this 10 μl assay a revised protocol was used. This involved the use of only 100 nl of standard or test compound per well of a 384-well plate and 1.5 μg membrane and 100 μg Leadseeker WGA beads. For the low volume protocol, membrane, beads and [³⁵S]-GTPγS were mixed together and then 10 μl of this mix were dispensed to each well. Incubation and plate read were identical for the 10 μl and 50 μl assays.

All exemplified compounds were tested in one or both of the [³⁵S]-GTPγS binding assays described above (i.e. the 10 μl and 50 μl assays).

Data was analysed by curve fitting as carried out using a Four Parameter Logistical equation using the XC50 software package (max 2 points deleted from any one curve). Specific binding is expressed as pEC₅₀ and as % efficacy compared to the maximal response of nicotinic acid binding.

In-Vivo Testing

HM74A agonists can be tested in male Spague-Dawley rats (200-250 g) which have been fasted for at least 12 hours prior to the study. The compounds are dosed intravenously at either 1 or 3 mg/kg (5 ml/kg) or by oral gavage at doses ranging from 1-30 mg/kg (10 ml/kg). Blood samples (0.3 ml tail vein bleed) can be taken pre-dose and at three times post-dose (times ranging from 15 minutes to 6 hours post-dose). Each blood sample is transferred to a heparin tube (Becton Dickinson Microtainer, PST LH) and centrifuged (10,000 g for 5 minutes) to produce a plasma sample. The plasma samples are assayed for levels of non-esterified fatty acids (NEFA) using a commercially available kit (Randox). Inhibition of plasma NEFA levels, relative to pre-dose levels, are used as a surrogate for HM74A agonist activity.

In order to determine whether HM74A compounds exhibit the flushing response associated with nicotinic acid they can be dosed to conscious guinea-pigs. Male Dunkin Hartley guinea pigs (300-600 g; n=10-20 per group) are fasted for at least 12 hours, but not in excess of 24 hours prior to experimention. Pre-study blood samples (0.5 ml) are taken from each animal by cardiac puncture under recovery anaesthesia (Isoflurane 3.5% with additional O2 (1 L/min)). Ear temperature measurements are taken by placing the left ear of each animal over an infra-red temperature probe. Measurements are taken at one minute intervals from 5 minutes pre-dose to 30 minutes post-dose. Temperature measurements are then taken at 15 minute intervals up to 2 hours post-dose. Animals receive test compounds by oral gavage (5 ml/kg). Blood samples (0.5 ml) are taken by cardiac puncture under terminal anaesthesia. Blood samples are taken from individual animals to provide data at 0.5, 1, 2, 3, and 4 hours post-dose. All blood samples are placed on a blood roller for 5 minutes then stored on ice until the end of the study. Following centrifugation (12000 g for 5 min) the plasma is transferred into fresh tubes and stored at −20° C. until assayed for NEFA concentrations.

Compounds according to Formula (I) have been synthesised (see synthetic examples below) and tested in the [³⁵S]-GTPγS binding assays discussed above.

Some compounds according to formula (I) including:

-   3-butyl-8-chloro-[3-(dimethylamino)propyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-3-(3,3-dimethylbutyl)-1-[2-(ethyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione; -   3-butyl-8-chloro-1-[3-(5-phenyl-1,2,4-oxadiazol-3-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione; -   1-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione; -   2-({4-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]phenyl}oxy)ethyl     acetate.     have utility as intermediates in the production of other compounds     according to formula (I).

The exemplified compounds (Examples 1-894) have a pEC₅₀ of 4.3 (+/−0.3 log unit) or greater and an efficacy of 30% or greater (in relation to nicotinic acid) in the [³⁵S]-GTPγS binding assays described above, in which they were tested.

The following compounds were tested and found to have activity lower than a pEC₅₀ of 4.3 (+/−0.3 log unit) and an efficacy of less than 30% (in relation to nicotinic acid) in the [³⁵S]-GTPγS binding assays described above, in which they were tested.

-   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[2-(1-piperidinyl)ethyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[2-(hexahydro-1H-azepin-1-yl)ethyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[2-(1-pyrrolidinyl)ethyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[2-(dimethylamino)-2-methylpropyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[3-(dimethylamino)propyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[3-(4-methyl-1-piperazinyl)propyl]-3,7-dihydro-1H-purine-2,6-dione; -   8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-[2-(dimethylamino)ethyl]-3,7-dihydro-1H-purine-2,6-dione

General Purification and Analytical Methods: LC/MS: Method

Analytical HPLC was conducted on a Supelcosil™ ABZ+PLUS column (Supelco) (3 μm, 3.3 cm×4.6 mm ID) eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solvent A), and 95% MeCN and 5% water (containing 0.5% HCO₂H) (solvent B), using the following elution gradient 0-0.7 min 0% B, 0.7-4.2 min 0→100% B, 4.2-4.6 minutes 100% B, 4.6-4.8 min 100→0% B at a flow rate of 3 ml/min. The diode array UV detection was carried out in the range 215 to 330 nm. The mass spectra (MS) were recorded on a Waters ZQ mass spectrometer using electrospray positive ionisation [(ES+ve to give MH⁺ and M(NH₄)⁺ molecular ions] or electrospray negative ionisation [(ES-ve to give (M-H)⁻ molecular ion] modes. Only the parent ion of major isotopes quoted.

¹H NMR spectra were recorded using a Bruker DPX 400 MHz spectrometer using tetramethylsilane as the standard.

Biotage™ chromatography refers to purification carried out using either the Flash 40i or Flash 150i purification systems, sold by Biotage AB, using cartridges pre-packed with KPSil (silica).

Companion™ system refers to the Teledyne Isco Combiflash Companion™ purification system. This is a gradient controlled purification system with integral, variable wavelength UV detection with the capability to trigger automated fraction collection by UV threshold.

Mass directed autoprep (MDAP) refers to methods where the material was purified by high performance liquid chromatography using either a Supelcosil ABZ+5 μm column (10 cm×20 mm i.d.) or a Supelcosil ABZ+10 μm column (15 cm×30 mm i.d.) with a suitable gradient of solvent A: 0.1% HCO₂H in water and solvent B: 95% MeCN, 5% water (containing 0.5% HCO₂H). The Waters 2767 inject/collector was triggered by a MicroMass ZQ Mass Spectrometer on detecting the mass of interest (using Micromass MassLynx software).

Preparative HPLC (Autoprep HPLC or Autoprep) refers to methods where the material was purified by high performance liquid chromatography on a Supelcosil ABZ+5 μm column (10 cm×21.2 mm i.d.) with a suitable gradient of 0.1% HCO₂H in water and MeCN (with 0.5% HCO₂H). The Gilson 233 fraction collector was triggered by UV detection.

SPE (solid phase extraction) refers to the use of polyethylene cartridges which are pre-packed with sorbent used for purification. The sorbent contained in these cartridges will be specified. Examples used are detailed below:

C18 SPE refers to the use of cartridges pre-packed with 40 μM C18 funtionalised silica sorbent (sold by Varian Inc.). The compound was loaded, typically in 50:50 DMSO/MeOH, onto a cartridge previously conditioned with MeCN and equilibrated with 5% MeCN in water. The product was eluted with a suitable gradient of 0.1% HCO₂H in water and MeCN (0.5% HCO₂H).

Aminopropyl SPE or column refers to the use of cartridges pre-packed with 40 μm-120 μm aminopropyl functionalized silica (sold by Varian Inc.). The crude product is typically loaded in DCM/MeOH mixtures onto a cartridge previously conditioned with MeOH. The neutral components were eluted with MeOH and/or DCM (3 or 4 column volumes) and the acidic components usually eluted with an eluent containing a proportion of AcOH (2-20%).

Oasis™ Cartridges/Oasis™ SPE's refer to SPE cartridges packed with a polymeric sorbent manufactured by the Waters Corporation. These are typically conditioned with 3 column volumes of MeOH and equilibrated with water before the sample is loaded. Salts and inorganics are eluted with water and the product typically eluted with MeOH or MeCN.

GreenHouse™ refers to a 24 reaction parallel synthesiser platform available from RDT Ltd, UK

As indicated above, compounds of Formula (I) may find use in human or veterinary medicine, for example as activators of HM74A, in the management of dyslipidaemia and hyperlipoproteinaemia.

Thus, there is provided as another embodiment of the present invention at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, for use in human or veterinary medicine, for example in the treatment of disorders of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa and obesity. As such, the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke.

There is provided as a further embodiment of the present invention at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment of disorders of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such, the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke.

It will be appreciated that references herein to treatment extend to prophylaxis, prevention of recurrence and suppression of symptoms as well as the treatment of established conditions.

In one embodiment of the invention, there is provided at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of disorders of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia. For example, the use is provided of at least one compound of Formula (I) or a pharmaceutically acceptable derivative thereof in the treatment of diabetic dyslipidaemia, mixed dyslipidaemia, heart failure, hypercholesteraemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke and cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.

It is to be understood that this embodiment of the present invention includes any combination of particular embodiments and covers all combinations of particular substituents described herein above for compounds of Formula (I).

Additionally, the present invention provides the use of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of inflammatory diseases or conditions of the joint, for example, arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or of the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, the enteropathy provoked by non-steroidal anti-inflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of the pancreas, (e.g. inflammation associated with diabetes melitus and complications thereof, of the kidney (e.g. glomerulonephritis), of the skin (e.g. dermatitis, psoriasis, eczema, urticaria, burn injury), of the eye (e.g. glaucoma) as well as of transplanted organs (e.g. rejection) and multi-organ diseases (e.g. systemic lupus erythematosis, sepsis) and inflammatory sequelae of viral or bacterial infections and inflammatory conditions associated with atherosclerosis and following hypoxic or ischaemic insults (with or without reperfusion), for example in the brain or in ischaemic heart disease.

In a further or alternative embodiments there is provided a method for the treatment of a human or animal subject with a condition where under-activation of the HM74A receptor contributes to the condition or where activation of the receptor will be beneficial, which method comprises administering to said human or animal subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof.

Again, it is to be understood that this embodiment of the present invention includes any combination of particular embodiments and covers all combinations of particular substituents described herein above for compounds of Formula (I).

In one embodiment, the present invention provides a method for the treatment of disorders of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa and obesity, which method comprises administering to said human or animal subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof. As such, these compounds may also find favour in methods for the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, which methods comprise administering to said human or animal subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof.

The amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof which is required to achieve the desired biological effect will, of course, depend on a number of factors, for example, the mode of administration and the precise clinical condition of the recipient. In general, the daily dose will be in the range of 0.1 mg-1-g/kg, typically 0.1-100 mg/kg. An intravenous dose may, for example, be in the range of 0.01 mg to 0.1 g/kg, typically 0.01 mg to 10 mg/kg, which may conveniently be administered as an infusion of from 0.1 μg to 1 mg, per minute. Infusion fluids suitable for this purpose may contain, for example, from 0.01 μg to 0.1 mg, per millilitre. Unit doses may contain, for example, from 0.01 μg to 1 g of a compound of the invention. Thus ampoules for injection may contain, for example, from 0.01 μg to 0.1 g and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 0.1 mg to 1 g, for example from 5 mg to 50 mg.

A compound of formula (I) or a pharmaceutically acceptable derivative thereof may be employed as the compound per se in the treatment of a disease where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, an example of this is where a compound of the present invention is presented with an acceptable carrier in the form of a pharmaceutical formulation. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with the compound of the invention as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the compound of the invention.

The formulations include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration.

There is also provided according to the invention a process for preparation of such a pharmaceutical composition which comprises mixing the ingredients.

Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of a a compound of formula (I) or a pharmaceutically acceptable derivative thereof; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. In general, the formulations are prepared by uniformly and intimately admixing the compound of formula (I) or a pharmaceutically acceptable derivative thereof, with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or moulding a powder or granules of the compound of formula (I) or a pharmaceutically acceptable derivative thereof optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.

Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the invention in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the compound of the invention in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, the formulation may be isotonic with the blood of the intended recipient. These preparations could be administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound of formula (I) or a pharmaceutically acceptable derivative thereof with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the compound of formula (I) or a pharmaceutically acceptable derivative thereof.

Thus, formulations of the present invention suitable for parenteral administration comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents. Examples of formulations suitable for oral administration include formulations comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof, in 10% DMSO and 90% sodium hydrogen carbonate in sterile saline. Examples of formulations suitable for intravenous administration include formulations comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof, in 5% or 10% DMSO and 95% or 90% sodium hydrogen carbonate in sterile water. Alternatively, the therapeutically active agent may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.

Formulations suitable for rectal administration may be presented as unit-dose suppositories. These may be prepared by admixing a a compound of formula (I) or a pharmaceutically acceptable derivative thereof with one or more conventional solid carriers, for example, cocoa butter or glycerides and then shaping the resulting mixture.

Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The compound of formula (I) or a pharmaceutically acceptable derivative thereof is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops).

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol. Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.

Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2-tetrafluorethane, carbon dioxide or other suitable gas.

Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin, may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example in combination with other classes of dyslipidaemic drugs (e.g. statins, fibrates, bile-acid binding resins or nicotinic acid).

The compounds of the instant invention may be used in combination with one or more other therapeutically active agents for example in combination with other classes of dyslipidaemic drugs e.g. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) or fibrates or bile acid binding resins or nicotinic acid. The invention thus provides, in a further embodiment, the use of such a combination in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial and the use of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the combination therapy of disorders of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa and obesity.

When the compounds of the present invention are used in combination with other therapeutically active agents, the compounds may be administered either together or separately, sequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further embodiment of the invention. The individual components of such combinations may be administered either together or separately, sequentially or simultaneously in separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that the two components must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.

When in combination with a second therapeutic agent active against the same disease, the dose of each component may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

The invention thus provides, in a further embodiment, a combination comprising at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof together with another therapeutically active agent.

The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further embodiment of the invention.

The compounds of the present invention and pharmaceutically acceptable derivatives thereof may be prepared by the methodology described hereinafter, constituting a further embodiment of this invention.

In one embodiment the present invention provides a method for the preparation of compound(s) of formula (I) from an appropriate starting material, for example compound(s) of formula (II):

wherein PG=protecting group, the method comprising:

-   -   (i) alkylation at N1 of an N7 protected xanthine;     -   (ii) alkylation at N3 of an N7 protected xanthine;     -   (iii) halogenation at C8; and     -   (iv) de-protection of N7;         in any order providing de-protection is carried out after         alkylation.

Process 1:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates a cycloalkyl, heterocyclyl, cycloalkenyl, heteroaryl or aryl.

i) Alkylation of guanine with allyl bromide ii) Diazotisation with sodium nitrite followed by hydrolysis to form the xanthine iii) Chlorination

iv) Alkylation at N3 v) Alkylation at N1

vi) Palladium catalysed removal of the allyl group wherein L represents a leaving group, for example halogen.

Process 2:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates an amide, carbamate or urea

-   wherein L represents a leaving group, for example halogen, d     represents (m−1) (i.e. d together with the preceding methylene=m), R     represents -(alkylene)_(n)-Y and Q may or may not be present, and if     present represents either O or NR5.

Process 3:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates a ‘reverse’ carbamate or ester

wherein L represents a leaving group, for example halogen, d represents (m−1), and R represents -(alk)_(n)-Y.

Process 4:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates an ester or amide

wherein L represents a leaving group, for example halogen, d represents (m−1), and R represents —NR⁵R⁷ or —OR⁵.

Process 5:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates a pyrazole, imidazole or tetrazole.

wherein L represents a leaving group, for example halogen, d represents (m−1), and R represents -(alk)_(n)-Y.

Process 6:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates an oxadiazole.

wherein L represents a leaving group, for example halogen, d represents (m−1), R represents an alkyl group and R′ represents -(alk)_(n)-Y.

Process 7:

A process according to the invention for preparing compound(s) of formula (I) in which R1 incorporates an oxadiazole

wherein L represents a leaving group, for example halogen, d represents (m−1), R represents an alkyl group and R′ represents -(alk)_(n)-Y.

Process 8:

A process according to the invention for preparing compound(s) of formula (I) in which R³ is CN comprises steps (i) and (ii) of Process 1 followed by:

iii) Alkylation at N3

iv) Alkylation at Ni

v) Formation of aldehyde at C8 by lithiation with LiHMDS and DMF quench vi) Conversion of the aldehyde to the nitrile vii) Palladium catalysed removal of the allyl group , wherein L represents a leaving group.

Process 9:

A process according to the invention for preparing compound(s) of formula (I) in which R³ is Cl or Br comprises steps (i) to (iv) of Process 8 followed by:

i) Halogenation at C8 using NCS or NBS ii) Palladium catalysed removal of the allyl group

Process 10:

A process according to the invention for preparing compound(s) of formula (I) in which R³ is CN comprises steps (i) to (iv) of Process 8 followed by:

v) Formation of ester vi) Hydrolysis of the methyl ester vii) Conversion of the acid to the amide. viii) Conversion of the amide to the nitrile ix) Palladium catalysed removal of the allyl group

Process 11:

A process according to the invention for preparing compound(s) of formula (I) in which R³ is Cl comprises:

i) Alkylation at N3 ii) Alkylation at N1

iii) Debenzylation iii) Chlorination at C8 wherein L represents a leaving group

Process 12:

A process according to the invention for preparing compound(s) of formula (I) in which R¹ differs from R² and R³ is Cl comprises steps (i) to (v) of Process 1 (where R² from process 1 is specifically SEM or MEM) followed by:

vi) Cleavage of MEM or SEM protecting group group vii) Alkylation of N3 followed by palladium catalysed removal of the allyl group wherein L represents a leaving group

Process 13:

A process according to the invention for preparing compound(s) of formula (I) in which R³ is Cl, Br or I comprises steps (i) to (iv) of Process 8 followed by:

v) Palladium catalysed removal of allyl group vi) Halogenation at C8 using NCS, NBS or NIS

Process 14:

A process according to the invention for preparing compound(s) of formula (I) comprises:

i) Pyrimidinedione formation

ii) Alkylation at N1

iii) Nitrosation iv) Reduction using Na₂S₂O₄ or a similar reducing agent v) Xanthine formation vi) Halogenation at C8 using NCS wherein L represents a leaving group

Process 15:

A process according to the invention for preparing compound(s) of formula (I):

wherein L represents a leaving group.

As an additional step to the general processes described above, and in particular for use in the preparation of the examples below, there are several ways of purifying resulting compounds, one or more of which may be of use in the present invention, for example the use of MDAP, by recrystallisation from one or more suitable solvents such as ethyl acetate, absolute ethanol, acetonitrile or methanol, or by use of purification column such as Silica Redisep cartridges and subsequent eluting with a suitable solvent such as dichloromethane containing ethyl acetate.

Where desired or necessary, as a final stage in any of the above synthetic processes, a resultant compound of formula (I) can be converted into a pharmaceutically acceptable salt form or vice versa or converting one salt form into another pharmaceutically acceptable salt form.

ABBREVIATIONS

-   AcOH Acetic acid -   atm Atmosphere -   br Broad (NMR) -   CDI Carbonyldiimidazole -   d Doublet (NMR) -   DBAD Di-t-butylazodicarboxylate -   DCM Dichloromethane -   DIPEA Diisopropylethylamine -   DMSO Dimethylsulfoxide -   DMF N,N-Dimethylformamide -   EtOAc Ethyl acetate -   EtOH Ethanol -   h Hour(s) -   IPA Isopropyl alcohol -   m Multiplet (NMR) -   MDAP Mass directed autoprep -   MeCN Acetonitrile -   MeOH Methanol -   min Minute(s) -   NCS N-Chlorosuccinimide -   NBS N-bromosuccinimide -   NIS N-iodosuccinimide -   q Quartet (NMR) -   rt Room temperature -   RT Retention time -   s Singlet (NMR) -   SPE Solid phase extraction cartridge -   t Triplet (NMR) -   TFA Trifluoroacetic acid -   THF Tetrahydrofuran -   DMEM Dulbecco's Modified Eagle's Medium -   HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulphonic acid -   LiHMDS Lithium hexamethyldisilylamide -   Δ Heat -   SEM 2-(trimethylsilyl)ethoxymethyl -   MEM 2-methoxyethoxymethyl -   Boc t-butoxycarbonyl -   THP tetrahydropyran

BRIEF DESCRIPTION OF FIGURES

FIG. 1: XRPD data of substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 1.

FIG. 2: XRPD data of substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione form 2.

FIG. 3: Overlay of XRPD data for substantially crystalline 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione Form 1 and Form 2.

The following non-limiting examples illustrate the present invention:

SYNTHETIC EXAMPLES

It should be noted that the assignment of (Z)-stereochemistry set out in the compounds exemplified below has not been confirmed by experimental data. The person skilled in the art will also recognise that there can be interconversion between E & Z isomers. (Dondoni, Alessandro; Lunazzi, Lodovico; Giorgianni, Patrizia; Macciantelli, Dante. Carbon-nitrogen rotational barrier as a stereochemical probe of benzamidoximes. Journal of Organic Chemistry (1975), 40(20), 2979-80)

Example 1 8-Chloro-1-(2-hydroxyethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-(2-hydroxyethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 5.1 mmol), Cs₂CO₃ (1.8 g, 5.6 mmol) and 2-chloroethanol (509 μL, 7.7 mmol) were reacted together in DMF (20 ml) at 60° C. for 18 h. The reaction was allowed to cool to it and the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (428 mg, 0.37 mmol) was added and the mixture degassed once more. Morpholine (2.1 ml, 24.7 mmol) was added and the mixture was stirred under nitrogen for 3 h, and then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The residue was taken up into MeOH and then passed down an aminopropyl column with the product eluting with 3% AcOH/MeOH. The product fractions were combined and concentrated then purified by recrystallisation from EtOAc. The resulting solid was collected by filtration and washed with EtOAc to give the title compound as a white solid (713 mg, 47%).

LC/MS: m/z 301 [MH]⁺, RT 2.7 min.

¹H NMR (DMSO-d₆) δ: 0.86 (t, 3H, J=7 Hz), 1.22-1.36 (m, 4H), 1.63 (m, 2H), 3.50 (br t, 2H, J=6 Hz), 3.90 (t, 2H, J=7.5 Hz), 3.95 (t, 2H, J=6.5 Hz), 4.75 (br s, 1H), 14.5 (br s, 1H).

b) 8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.44 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (0.051 g, 0.484 mmol). After 10 min stirring at rt pentyl iodide (0.063 ml, 0.484 mmol) was added and stirring continued under nitrogen at rt for 18 h. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO₄) filtered and evaporated. Purification by SPE (Si, 5 g) eluting with 4:1 EtOAc/cyclohexane afforded the title compound as a white solid (96 mg, 74%).

LC/MS: m/z 297 [MH]⁺.

c) 8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

To a solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione) (10.52 g, 54.7 mmol) in anhydrous DMF (60 ml) was added NCS (8.04 g, 60.2 mmol). The reaction mixture was left to stir under nitrogen at 20° C. for 6 h. The reaction mixture was concentrated in vacuo to give an amber oil. MeOH was added and left to stand for 18 h. The resulting residue was filtered and dried under vacuum to give the title compound (7.69 g, 62%).

LC/MS: m/z 227 [MH]⁺.

d) 7-(2-Propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

A mixture of 2-amino-7-(2-propen-1-yl)-1,7-dihydro-6H-purin-6-one (40 g, 0.209 mol) in AcOH (900 ml) and water (100 ml) was heated at 55° C. Sodium nitrite (57.74 g, 0.837 mol) in water (100 ml) was added dropwise. Care; toxic fumes. After the addition was complete (ca. 25 min) the reaction mixture was allowed to cool to ambient temperature and then concentrated to ca. ⅓ of its original volume. Water (500 ml) was added and the resulting precipitate collected by filtration. The residue was washed with water then dried at 50° C. over P₂O₅ and under vacuum for 2 h to give the title compound (17.20 g). The aqueous fraction was concentrated and water added (100 ml). Again the resulting solid was filtered and dried. This gave more of the title compound (2.31 g). Combined product (19.52 g, 49%).

LC/MS: m/z 193 [MH]⁺.

e) 2-Amino-7-(2-propen-1-yl)-1,7-dihydro-6H-purin-6-one

A mixture of guanosine (20 g, 0.071 mol), allyl bromide (14.7 ml, 0.169 mol) and anhydrous DMSO (100 ml) was stirred at rt, under nitrogen, for 18 h. Conc. HCl (50 ml of 37%) was added in one portion and the mixture stirred for 45 min then poured into MeOH (600 ml). The methanolic solution was neutralised with 2M NaOH (aq) solution and the resulting white precipitate collected by filtration. The white solid was dried under vacuum at 50° C. for 18 h to afford the title compound (16 g) which was used without further purification.

LC/MS: m/z 192 [MH]⁺.

Example 2 8-Chloro-3-(2-cyclobutylethyl)-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione

7-(2-Propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (575 mg, 2.54 mmol) was stirred in dry THF (20 ml) with 2-cyclobutylethanol (c.73 mol %, remainder 1-butanol) (254 mg). Dibenzyl azodicarboxylate (94%, 1.57 g, 4.95 mmol) was added, the mixture cooled to 0° C. and a solution of triphenylphosphine (1.302 g, 4.97 mmol) in dry THF (10 ml) was added dropwise. The mixture was stirred for 30 min. at 0° C. then at rt for 18 h under nitrogen. The solvent was evaporated and the residue purified on a Biotage system (100 g) eluting with EtOAc-cyclohexane (2:3). The material thus obtained (0.53 g) was a mixture of the required compound, the corresponding n-butyl analogue and dibenzyl hydrazinedicarboxylate, and was alkylated without further purification.

This mixture (256 mg) and Cs₂CO₃ (326 mg, 1 mmol) were stirred in dry DMF (5 ml). 2-Chloroethanol (80.5 mg, 1 mmol) was added and the mixture was stirred and heated at 55° C. for 65 h. After cooling, it was thoroughly degassed, tetrakis(triphenylphosphine)palladium(0) (200 mg) and morpholine (0.7 ml) were added, and the mixture was stirred for 6 h. EtOAc and 2M HCl were added and the mixture filtered, the organic phase washed with brine, dried (Na₂SO₄) and evaporated and the residue separated from non-acidic material by aminopropyl SPE (5 g, MeOH-THF and MeOH wash, elution with DCM-MeOH with 5% added AcOH). The material obtained from the acid wash (105 mg) was further purified by MDAP to provide the title compound (42.7 mg).

LC/MS: m/z 313 [MH]⁺, RT 2.58 min.

¹H NMR (DMSO-d₆) δ: 1.53-1.64 (m, 2H), 1.71-1.84 (m, 4H), 1.94-2.02 (m, 2H), 2.21-2.30 (m, 1H), 3.47-3.53 (m, 2H), 3.84 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), 4.76 (br s, 1H), 14.45 (br s, 1H)

Example 3 8-Chloro-1-[3-(2-furanyl)propyl]-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, sodium salt

A GreenHouse™ tube equipped with a stirrer was charged with a 0.25 ml aliquot of a 0.54M solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.13 mmol) in THF. To the mixture was added 3-(2-furanyl)-1-propanol (21 mg, 0.16 mmol, 1.2 eq) in THF (0.25 ml), followed by a 0.25 ml aliquot of a 0.71M solution of bis(1,1-dimethylethyl) (E)-1,2-diazenedicarboxylate (0.18 mmol) in THF and then a 0.25 ml aliquot of a 0.71M solution of triphenylphosphine (0.18 mmol) in THF. The solution was stirred in a GreenHouse™ under nitrogen for 16 h. To the mixture was added a further 0.25 ml aliquot of a 1.4M solution of bis(1,1-dimethylethyl) (E)-1,2-diazenedicarboxylate (0.36 mmol) in THF and then a further 0.25 ml aliquot of a 1.4M solution of triphenylphosphine (0.36 mmol) in THF. The mixture was stirred for 16 h under a stream of nitrogen.

Tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) and morpholine (0.12 ml, 1.35 mmol) were added to the mixture which was stirred for 16 h under a stream of nitrogen. The reaction mixture was concentrated under nitrogen and the crude material dissolved in aqueous NaOH solution (0.5 ml, 2M). The resulting solution was purified using aminopropyl SPE (eluting with AcOH in DCM and MeOH). Further purification using C18 SPE (eluting with a water, ammonia and MeCN mixture) afforded the title compound as a clear gum (22 mg, 45%).

LC/MS: m/z 365 [MH]⁺, RT 3.48 min.

NMR (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz), 1.35-1.19 (m, 4H), 1.62 (m, 2H), 1.79 (m, 2H), 2.59 (t, 2H, J=8 Hz), 3.93-3.80 (m, 4H), 6.14 (d, 1H, J=3 Hz), 6.32 (dd, 1H, J=3 and 2 Hz), 7.48 (d, 1H, J=2 Hz).

Example 4 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(3-methylphenyl)methyl]pentanamide a) 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(3-methylphenyl)methyl]pentanamide

A mixture of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) in DCM (3 ml) was treated with CDI (27 mg, 0.17 mmol) and left to stir at rt for 1 h. [(3-Methylphenyl)methyl]amine (25 μl, 0.20 mmol) was added and left to stir for a further 1 h. The mixture was concentrated then purified by aminopropyl SPE. The title compound was eluted with 2-3% AcOH/MeOH then concentrated to give the title compound as a white solid (56 mg, 87%).

LC/MS: m/z 460 [MH]⁺, RT 3.3 min.

b) 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid

A mixture of methyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (8.40 g, 0.023mol), LiOH (1.63 g, 0.068mol), MeOH (150 ml) and water (10 ml) was left to stir at ambient temperature for 64 h. The mixture was partitioned between water and EtOAc and the aqueous acidified. The organic layer was separated and the aqueous extracted again with EtOAc. The combined extracts were washed with brine, dried (MgSO₄) and concentrated, giving the title compound as an off-white solid (9.09 g).

LC/MS: m/z 357 [MH]⁺, RT 3.0 min.

c) Methyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate

A solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 6.7 mmol) in anhydrous DMF (40 ml) was treated with Cs₂CO₃ (2.42 g, 7.4 mmol) and methyl 5-bromovalerate (1.16 ml, 8.1 mmol). The mixture was heated at 50° C. for 18 h then allowed to cool to rt and degassed under a gentle vacuum, then nitrogen introduced. This was repeated twice. Pd(PPh₃)₄ (779 mg, 0.67 mmol) was added and the mixture degassed once more. Morpholine (5.9 ml, 67 mmol) was added and left to stir for 3 h at rt. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow residue/oil (5.16 g). The residue was taken up in MeOH and divided into two equal portions, and then each passed down an aminopropyl SPE (20 g), eluting with MeOH followed by 5% AcOH/MeOH then 10% AcOH/MeOH and finally 15% AcOH/MeOH. The product fractions were combined and concentrated giving the title compound as an off-white solid (2.28 g, 91%).

LC/MS: m/z 371 [MH]⁺, RT 3.1 min.

Example 5 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(3-ethylphenyl)methyl]pentanamide

A mixture of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) in DCM (3 ml) was treated with CDI (27 mg, 0.17 mmol) and left to stir at rt for 1 h. [(3-ethylphenyl)methyl]amine (25 μl 0.20 mmol) was added and left to stir for a further 1 h. The mixture was concentrated then purified on an aminopropyl SPE. The title compound was eluted with 2-3% AcOH/MeOH to give a white solid (61 mg, 92%).

LC/MS: m/z 474 [MH]⁺, RT 3.5 min.

Example 6 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(4-fluoro-3-methylphenyl)methyl]pentanamide

A mixture of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) and DCM (3 ml) was treated with CDI (27 mg, 0.17 mmol) and stirred at rt for 1 h. 1-(4-Fluoro-3-methylphenyl)methanamine (27 mg, 0.20 mmol) and DIPEA (24 μl 0.14 mmol) were added. After 1 h the mixture was concentrated and then the residue taken up into MeOH and passed down an aminopropyl SPE. The product was eluted with 2% AcOH/MeOH and further purified by MDAP to give the title compound as a solid (15 mg, 22%).

LC/MS: m/z 478 [MH]⁺, RT 3.4 min.

Example 7 Phenylmethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate

A mixture of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) in DCM (3 ml) was treated with CDI (27 mg, 0.17 mmol) and left to stir at rt for 1 h. Benzyl alcohol (21 μl, 0.20 mmol) was added and left to stir for a further 1 h. The reaction mixture was concentrated and DMF (3 ml) was added then heated at 50° C. for 2 h. The mixture was concentrated then purified by MDAP giving the title compound as a white solid (33 mg, 53%).

LC/MS: m/z 447 [MH]⁺, RT 3.7 min.

Example 8 (3-Methylphenyl)methyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate a) (3-Methylphenyl)methyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

A solution of 3-methylbenzyl alcohol (16 μl, 0.13 mmol) in DCM (3 ml) was treated with CDI (24 mg, 0.15 mmol) and allowed to stir at rt for 1 h. 1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione trifluoroacetate (50 mg, 0.16 mmol) was added followed by DIPEA (28 μl, 0.16 mmol) then heated at 50° C. for 56 h. The reaction mixture was concentrated, the residue taken up into MeOH and purified by aminopropyl SPE. The title compound eluted with 2% AcOH/MeOH and a white solid collected (40 mg, 58%).

LC/MS: m/z 462 [MH]⁺, RT 3.6 min.

b) 1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione trifluoroacetate

A solution of 1,1-dimethylethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate (1.59 g, 4.38 mmol) in DCM (16 ml) was treated with TFA (16 ml) and stirred at rt for 2 h then concentrated in vacuo. Residual TFA was removed by azeotroping with DCM then the residue was triturated with Et₂O to give the title compound as a solid (1.48 g, quant.).

LC/MS: m/z 314 [MH]⁺, RT 2.1 min.

c) 1,1-Dimethylethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

A solution of 1,1-dimethylethyl (3-hydroxypropyl)carbamate (1.0 ml, 6.1 mmol) in THF (40 ml) was treated with 8-chloro-3-pentyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 5.1 mmol) and PPh₃ (1.73 g, 6.6 mmol) at rt under nitrogen. DBAD (1.52 g, 6.6 mmol) was added in one portion and stirred for 18 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (586 mg, 0.51 mmol) was added and the mixture degassed once more. Morpholine (4.4 ml, 50.7 mmol) was added and the mixture was stirred under nitrogen for 3 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow oil. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 2-3% AcOH/MeOH. The product fractions were combined and concentrated, giving the title compound as a clear gummy solid (1.59 g, 75%).

LC/MS: m/z 414 [MH]⁺, RT 3.4 min.

Example 9 Phenylmethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione trifluoroacetate (50 mg, 0.12 mmol) in DCM (3 ml) was treated with DIPEA (51 μl, 0.29 mmol) and benzyl chloroformate (20 μl, 0.14 mmol). After 1 h the reaction mixture was concentrated and purified on an aminopropyl SPE. The title compound eluted with 2% AcOH/MeOH and a white solid collected (35 mg, 67%).

LC/MS: m/z 448 [MH]⁺, RT 3.4 min.

Example 10 (2-Fluorophenyl)methyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

(2-Fluorophenyl)methanol (11 μl, 0.10 mmol) in DCM (3 ml) was reacted with CDI (17 mg, 0.11 mmol) under nitrogen for 1 h. 1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione trifluoroacetate (50 mg, 0.16 mmol) was added followed by DIPEA (20 μl, 0.12 mmol) then heated at reflux for 18 h. THF (3 ml) was added and heated at 75° C. for 5 h. After cooling, the mixture was concentrated in vacuo and purified by MDAP to give the title compound as a solid (21 mg, 39%).

LC/MS: m/z 466 [MH]⁺, RT 3.4 min.

Example 11 (2,4-Difluorophenyl)methyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

(2,4-Difluorophenyl)methanol (11 μL, 0.10 mmol) in DCM (3 ml) was reacted with CDI (17 mg, 0.11 mmol) under nitrogen for 1 h. 1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione trifluoroacetate (50 mg, 0.16 mmol) was added followed by DIPEA (20 μl, 0.12 mmol) then heated at reflux for 18 h. THF (3 ml) was added and heated at 75° C. for 5 h. After cooling, the mixture was concentrated in vacuo and purified by MDAP to give the title compound as a solid (29 mg, 21%).

LC/MS: m/z 484 [MH]⁺, RT 3.4 min.

Example 12 2-(3-Pyridinyl)ethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate a) 2-(3-Pyridinyl)ethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

A solution of CDI (21 mg, 0.13 mmol) in THF (2 ml) was treated with 2-(3-pyridinyl)ethanol (16 mg, 0.13 mmol) and heated at reflux for 1 h before the addition of 1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione hydrochloride (50 mg, 0.14 mmol) and DIPEA (25 μl, 0.14 mmol). The reaction was left at reflux for 18 h then concentrated and purified by MDAP to provide the title compound as a solid (30 mg, 24%).

LC/MS: m/z 463 [MH]⁺, RT 2.6 min.

b) 1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione hydrochloride

A mixture of 1,1-dimethylethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate (5.19 g, 12.5 mmol) and 4M HCl in 1,4-dioxane (80 ml) was stirred at rt for 3 h. The mixture was concentrated in vacuo and dried under vacuum to provide the title product as a white solid (4.49 g, quant.).

LC/MS: m/z 314 [MH]⁺, RT 2.2 min.

Example 13 2-(3-Fluorophenyl)ethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

A solution of CDI (21 mg, 0.13 mmol) in THF (2 ml) was treated with 2-(3-fluorophenyl)ethanol (16 μl, 0.13 mmol) and heated at reflux for 1 h before the addition of 1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione hydrochloride (50 mg, 0.14 mmol) and DIPEA (25 μL, 0.14 mmol). The reaction was left at reflux for 18 h then concentrated and purified by MDAP to provide the title compound as a solid (27 mg, 39%).

LC/MS: m/z 480 [MH]⁺, RT 3.5 min.

Example 14 2-(2-Thienyl)ethyl [3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]carbamate

A solution of CDI (21 mg, 0.13 mmol) in THF (2 ml) was treated with 2-(2-thienyl)ethanol (15 μl, 0.13 mmol) and heated at reflux for 1 h before the addition of 1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione hydrochloride (50 mg, 0.14 mmol) and DIPEA (25 μL, 0.14 mmol). The reaction was left at reflux for 18 h then concentrated and purified by MDAP to provide the title compound as a solid (34 mg, 51%).

LC/MS: m/z 468 [MH]⁺, RT 3.4 min.

Example 15 3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl (1-phenylcyclopropyl)carbamate a) 3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl (1-phenylcyclopropyl)carbamate

A solution of 8-chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.16 mmol) was treated with CDI (28 mg, 0.18 mmol) and allowed to stir at rt for 1 h. 1-Phenylcyclopropanamine (30 mg, 0.20 mmol) was added and the mixture heated at reflux under nitrogen for 18 h. Another aliquot of 1-phenylcyclopropanamine (30 mg, 0.20 mmol) was added followed by THF (3 ml). The reaction was heated at 75° C. for 18 h then concentrated and purified by MDAP. This gave the title compound as a white solid (13 mg, 18%).

LC/MS: m/z 474 [MH]⁺, RT 3.5 min.

b) 8-Chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-3-pentyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3,7-dihydro-1H-purine-2,6-dione (5.87 g, 14.8 mmol) in EtOH (100 ml) was treated with pTsOH (2.8 g, 14.8 mmol) and stirred at rt for 18.5 h. The mixture was partitioned between 1M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted once more. The combined extracts were washed with water (×5), brine, then dried (MgSO₄) and concentrated, giving a pale yellow solid. The solid was washed with Et₂O and collected by filtration giving a white solid (2.42 g, 52%).

LC/MS: m/z 315 [MH]⁺, RT 2.7 min.

c) 8-Chloro-3-pentyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5.0 g, 16.8 mmol), Cs₂CO₃ (6.0 g, 18.5 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (3.4 ml, 20 mmol) were reacted together in DMF (100 ml) at 50° C. under nitrogen for 24 h. The reaction was allowed to cool to rt and the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (1.4 g, 1.2 mmol) was added and the mixture degassed once more. Morpholine (14.7 ml, 170 mmol) was added and the mixture was stirred under nitrogen for 3 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow residue (5.16 g). MeOH was added and then passed down an aminopropyl SPE with the product eluting with 5% AcOH/MeOH. The product fractions were combined and concentrated, giving the title compound as a pale yellow solid (5.97 g, 89%).

LC/MS: m/z 399 [MH]⁺, RT 3.3 min.

Example 16 3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl (phenylmethyl)carbamate

A solution of 8-chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.16 mmol) in THF (3 ml) was treated with triphosgene (47 mg, 0.16 mmol) and pyridine (13 μl, 0.16 mmol). After 30 min benzylamine (217 μl, 2.0 mmol) was added and left to stir for a further 30 min. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The residue was taken up into MeOH and purified by passing down an aminopropyl SPE, the product eluted with 2-5% AcOH/MeOH. The title compound was obtained as an off-white solid (67 mg, 94%).

LC/MS: m/z 448 [MH]⁺, RT 3.2 min.

Example 17 3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl [(3-methylphenyl)methyl]carbamate

A solution of 8-chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.16 mmol) in DCM (3 ml) was treated with CDI (31 mg, 0.19 mmol) and stirred at rt for 1 h. 3-Methylbenzylamine (26 μl, 0.21 mmol) was added and heated at reflux for 18 h. Another aliquot of methylbenzylamine (4 μl, 0.03 mmol) was added and the mixture left for 4 h at reflux. The mixture was concentrated then taken up into MeOH and passed down an aminopropyl SPE. The product was, eluted with 2% AcOH/MeOH and then purified further by MDAP. This gave the title compound as a white solid (42 mg, 57%).

LC/MS: m/z 462 [MH]⁺, RT 3.5 min.

Example 18 8-Chloro-1-(3-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-(3-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml) was stirred with sodium carbonate (64 mg, 0.6 mmol) and 2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at 45° C. for 18 h under nitrogen. After cooling to rt the mixture was degassed by evacuating and readmitting nitrogen, and stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303 mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated and the residue purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57 mg) as a solid.

LC/MS: m/z 507 [MH]⁺, RT 3.64 min.

b) 8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

3-Pentyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5 g, 16.86 mmol) and 3-(1H-pyrazol-4-yl)propan-1-ol (2.12 g, 16.8 mmol) were stirred in dry THF (150 ml) at 3° C. Dibenzyl azodicarboxylate (10.05 g, 33.7 mmol) was added followed by the dropwise addition of triphenylphosphine (8.83 g, 33.7 mmol) in dry THF (70 ml). The mixture was allowed to warm to rt and stirred for 18 h. Water (1 ml) was added and the solvents evaporated. The residue was taken up in Et₂O (200 ml) from which a white solid, mostly triphenylphosphine oxide, crystallised and was filtered off. The filtrate was concentrated and further by-products crystallised from ether-cyclohexane. The remaining filtrate was concentrated (19.2 g) and purified on a Biotage™ system (400 g) eluting with EtOAc-cyclohexane (2:1) to afford the title compound as a white solid (2.89 g).

LC/MS: m/z 405 [MH]⁺, RT 3.19 min.

The following compounds (Table 1) were prepared using a method analogous to that for Example 18, from the corresponding benzyl halides.

TABLE 1 Yield Example structure (mg) LC/MS: 19

68 m/z 509 [MH]⁺ RT 3.58 min 8-chloro-3-pentyl-1-(3-{1-[(2,4,6- trifluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 20

56 m/z 507 [MH]⁺ RT 3.73 min 8-chloro-1-(3-{1-[(2-chloro-4-fluorophenyl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 21

29 m/z 491 [MH]⁺ RT 3.53 min 8-chloro-1-(3-{1-[(2,6-difluorophenyl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 22

 32* m/z 473 [MH]⁺ RT 3.55 min 8-chloro-1-(3-{1-[(2-fluorophenyl)methyl]-1H-pyrazol- 4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione *after additional purification by MDAP. NMR Details for Selected Examples from Table 1

Example 19 8-chloro-3-pentyl-1-(3-{1-[(2,4,6-trifluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz), 1.20-1.40 (m, 4H), 1.60-1.70 (m, 2H), 1.70-1.82 (m, 2H), 2.39 (t, 2H, J=8 Hz), 3.83-3.94 (m, 4H), 5.24 (s, 2H), 7.18-7.30 (m, 3H), 7.57 (s, 1H).

Example 23 8-Chloro-1-(3-{1-[(2,4-difluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol) and sodium carbonate (85 mg, 0.8 mmol) were stirred in dry DMF (2 ml) with 2,4-difluorobenzyl bromide (166 mg, 0.8 mmol) at 45° C. for 18 h. The mixture was degassed and stirred with tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and morpholine (176 mg, 2 mmol) at rt for 6 h. The reaction was worked up and purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH, eluting with DCM-MeOH (1:1) with 5% added AcOH) to yield the title compound (37.7 mg) as a solid.

LC/MS: m/z 491 [MH]⁺, RT 3.42 min.

¹H NMR (d⁶ DMSO) 0.85 (3H, t, J=7 Hz), 1.21-1.34 (4H, m), 1.58-1.68 (2H, m), 1.71-1.80 (2H, m), 2.41 (2H, t, J=8 Hz), 3.84-3.93 (4H, m), 5.26 (2H, s), 7.02-7.09 (1H, m), 7.15-7.29 (2H, m), 7.31 (1H, s), 7.61 (1H, s).

The following compounds (Table 1) were prepared using a method analogous to that for Example 23, from the corresponding benzyl halides.

TABLE 2 Yield Example Structure (mg) LC/MS: 24

 17* m/z 455 [MH]⁺ RT 3.52 min 8-chloro-3-pentyl-1-{3-[1-(phenylmethyl)-1H-pyrazol-4- yl]propyl}-3,7-dihydro-1H-purine-2,6-dione 25

  11.6* m/z 489 [MH]⁺ RT 3.52 min 8-chloro-1-(3-{1-[(3-chlorophenyl)methyl]-1H-pyrazol-4- yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 26

33 m/z 469 [MH]⁺ RT 3.54 min 8-chloro-1-(3-{1-[(3-methylphenyl)methyl]-1H-pyrazol-4- yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 27

42 m/z 473 [MH]⁺ RT 3.44 min 8-chloro-1-(3-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-4- yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione *after additional purification by MDAP. NMR Details for Selected Examples from Table 2

Example 24 8-chloro-3-pentyl-1-{3-[1-(phenylmethyl)-1H-pyrazol-4-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.87 (t, 3H, J=7 Hz), 1.20-1.36 (m, 4H), 1.60-1.70 (m, 2H), 1.72-1.85 (m, 2H), 2.42 (t, 2H, J=8 Hz), 3.83-3.95 (m, 4H), 5.24 (s, 2H), 7.13-7.38 (m, 6H), 7.61 (s, 1H).

Example 28 8-Chloro-1-(3-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Prepared by the method for 8-chloro-1-(3-{1-[(2,4-difluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione but from 2-chlorobenzyl bromide (164 mg, 0.8 mmol). However, in order to complete the deprotection step further tetrakis(triphenylphosphine)palladium(0) (40 mg) and morpholine (0.15 ml) were added and stirring continued for a further 5.5 h. Purification by aminopropyl SPE as above afforded the title compound as a solid (42 mg).

LC/MS: m/z 489 [MH]⁺, RT 3.67 min.

Example 29 3-Butyl-8-chloro-1-{3-[1-(phenylmethyl)-1H-imidazol-4-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{3-[1-(phenylmethyl)-1H-imidazol-4-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (300 mg, 0.77 mmol) in anhydrous THF (5 ml) was treated with benzyl bromide (144 mg, 0.84 mmol) and DIPEA (147 μl, 0.84 mmol). The mixture was left to stir at rt under nitrogen for 4 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The crude was purified by a silica SPE column using a 0.5-5% MeOH/DCM gradient. The product fractions were combined and concentrated under high vacuum. The product was dissolved in THF (5 ml) then Pd(PPh₃)₄ (88 mg, 0.077 mmol) and morpholine (670 μl, 7.67 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. 88 mg of Pd(PPh₃)₄ (0.077 mmol) was added and the mixture was left to stir at rt under nitrogen for 16 h. The mixture was partitioned between EtOAc and H₂O. The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). The organic layers were combined, washed with brine, dried (MgSO₄) and concentrated. The crude product was purified by MDAP to give the title compound as a white solid (9 mg, 2%).

LC/MS: m/z 441 [MH]⁺, RT 2.50 min.

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7.5 Hz), 1.28 (m, 2H), 1.60 (m, 2H), 1.79 (m, 2H), 2.48 (t overlapping with DMSO, 2H, J=7.5 Hz), 3.89 (m, 4H), 5.17 (s, 2H), 7.08 (s, 1H), 7.31, (m, 6H), 8.03 (s, 1H).

b) 3-Butyl-8-chloro-1-[3-(1H-imidazol-4-yl)propyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.8 g, 9.9 mmol) in anhydrous THF (60 ml) was treated with 3-(1H-imidazol-4-yl)-1-propanol (1.5 g, 12 mmol) in anhydrous THF (10 ml) and PPh₃ (3.4 g, 13 mmol). DBAD (2.9 g, 13 mmol) was added in one portion and the mixture was left to stir at rt, under nitrogen for 18 h. The mixture was partitioned between EtOAc and H₂O. The aqueous layer was extracted and washed with EtOAc. The organic layers were combined, washed with brine, dried (MgSO₄) and concentrated. The crude product was purified by a silica SPE cartridge using a MeOH/EtOAc gradient (0.5%-7% MeOH). The product fractions were combined and concentrated by to give the title compound as a white solid (2.16 g, 55%).

LC/MS: m/z 391 [MH]⁺, RT 2.40 min.

c) 3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

To a solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.34 g, 13.4 mmol) in anhydrous DMF (19 ml) was added NCS (1.97 g, 14.8 mmol) and left to stir at rt under nitrogen for 22 h. The mixture was concentrated in vacuo to give a yellow solid which was filtered and washed with MeOH to provide a first crop. The filtrate was concentrated to a solid and washed with MeOH to provide a second crop and repeated a further two occasions to provide the title compound. On the final wash the filtrate was further purified by SPE (Si, 20 g) cartridge eluting with EtOAc:cyclohexane (1:1). The combined solids were dried under vacuum to afford the title compound (2.42 g, 64%).

LC/MS: m/z 283 [MH]⁺.

Example 30 3-Butyl-8-chloro-1-(3-{1-[(2,3-difluorophenyl)methyl]-1H-imidazol-4-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(bromomethyl)-2,4-difluorobenzene (54 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The crude product was purified on a silica SPE column using a DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh₃)₄ (39 mg, 0.034 mmol) and morpholine (200 μl, 2.3 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (14 mg, 7%).

LC/MS: m/z 477 [MH]⁺, RT 2.54 min.

Example 31 3-Butyl-8-chloro-1-[3-(1-{[2-(trifluoromethyl)phenyl]methyl}-1H-imidazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-2-(trifluoromethyl)benzene (61 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The crude product was purified on a silica SPE column using DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh₃)₄ (35 mg, 0.030 mmol) and morpholine (174 μl, 2.0 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (50 mg, 26%).

LC/MS: m/z 509 [MH]⁺, RT 2.64 min.

Example 32 3-Butyl-8-chloro-1-[3-(1-{[3-(trifluoromethyl)phenyl]methyl}-1H-imidazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-3-(trifluoromethyl)benzene (65 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The crude product was purified on a silica SPE column using a DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh₃)₄ (30 mg, 0.027 mmol) and morpholine (156 μl, 1.8 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (18 mg, 9%).

LC/MS: m/z 509 [MH]⁺, RT 2.78 min.

Example 33 3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (669 mg, 1.39 mmol) in THF (7 ml) was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (160 mg, 0.14 mmol) was added and the mixture degassed once more. Morpholine (1.2 ml, 13.9 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were washed with brine, dried (MgSO₄) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 2-3% AcOH/MeOH. The product fractions were combined and concentrated giving a pale yellow solid (380 mg). Approximately a quarter of the material was purified by autoprep HPLC and rest was crystallised from MeOH:DMSO (1:1) giving the title compound as a white solid (125 mg, 31%).

LC/MS: m/z 442 [MH]⁺, RT 3.0 min.

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7 Hz), 1.30 (m, 2H), 1.62 (m, 2H), 2.07 (m, 2H), 3.90 (m, 6H), 4.13 (t, 2H, J=7 Hz), 7.24 (m, 5H), 8.36 (1H, s), 14.5 (br s, 1H).

b) 3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-(phenylmethyl)-1H-1,2,4-triazole (2.1 g, 13.2 mmol) in MeOH (40 ml) was treated with 0.5M NaOMe in MeOH (29 ml) followed by 1,3-dibromopropane (1.7 ml). After stirring for 5 h at 50° C. the mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving an oily residue (1.0 g). To this was added butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (917 mg, 3.2 mmol) and Cs₂CO₃ (1.2 g, 3.6 mmol). DMF (15 ml) was added and the mixture was stirred at 50° C. for 20 h then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The resulting oil (1.52 g) was passed down a silica SPE (50 g) column eluting with EtOAc/cyclohexane mixtures. Two isomeric products of the triazole were obtained as a 2:1 mixture, in favour of the title compound, as a yellow paste (697 mg, 67% based on ratio of isomers present).

LC/MS: m/z 482 [MH]⁺, RT 3.3 min.

Example 34 8-Chloro-3-pentyl-1-{3-[5-(phenylmethyl)-2H-tetrazol-2-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 5-benzyl-1H-tetrazole (1.0 g, 6.24 mmol) in MeOH (5 ml) was treated with 1-chloro-3-iodopropane (1.0 ml, 9.36 mmol) and a solution of 0.5M NaOMe in MeOH (4.7 ml, 9.36 mmol). The reaction was heated at reflux for 18 h then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO₄) and concentrated, giving a yellow solid. (796 mg). 700 mg of this material was reacted with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (732 mg, 2.47 mmol) and Cs₂CO₃ (967 mg, 3.0 mmol) in DMF (20 ml) at 75° C. for 24 h. The reaction was allowed to cool to rt and the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (428 mg, 0.37 mmol) was added and the mixture degassed once more. Morpholine (2.1 ml, 24.7 mmol) was added and the mixture was stirred under nitrogen for 3 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted once more. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE, the product eluting with 2-3% AcOH/MeOH. The product fractions were combined and concentrated then purified by the MDAP to give the title compound as a white solid (35 mg, 3%).

LC/MS: m/z 457 [MH]⁺, RT 3.5 min.

¹H NMR; (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz), 1.21-1.34 (m, 4H), 1.62 (m, 2H), 2.22 (m, 2H), 3.88 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7 Hz), 4.17 (s, 2H), 4.67 (t, 2H, J=7 Hz), 7.20-7.32 (m, 5H), 14.5 (br s, 1H).

Example 35 3-Butyl-8-chloro-1-{3-[5-(phenylmethyl)-2H-tetrazol-2-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 5-benzyl-1H-tetrazole (1.8 g, 11.2 mmol) in MeOH (30 ml) was treated with 1,3-dibromopropane (5.7 ml, 56.2 mmol) and 0.5M NaOMe in MeOH (31.5 ml) then stirred at 40° C. under nitrogen for 60 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. Partial purification by SPE (20 g silica, cyclohexane/EtOAc mixtures) and by the Companion™ system (silica SPE, cyclohexane/EtOAc mixtures) gave an oil (1.98 g, 62% of a mixture of isomers, 2:1 in favour of 2-(3-bromopropyl)-5-(phenylmethyl)-2H-tetrazole) which was taken on crude in the next step.

A mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.74 g, 6.1 mmol), crude 2-(3-bromopropyl)-5-(phenylmethyl)-2H-tetrazole) (1.9 g, 6.8 mmol), Cs₂CO₃ (2.2 g, 6.8 mmol) and DMF (60 ml) was stirred at 45° C. under nitrogen for 24 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (705 mg, 0.61 mmol) was added and the mixture degassed once more. Morpholine (5.4 ml, 61.4 mmol) was added and the mixture was stirred under nitrogen for 4 h, and then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl column with the product eluting with 2% AcOH/MeOH. The product was further purified by the Companion™ system using EtOAc/cyclohexane mixtures. The resulting solid was stirred with boiling Et₂O and filtered after cooling to rt. The title compound was collected as a white solid (1.01 g, 37%) and dried at 50° C. under vacuum.

LC/MS: m/z 443 [MH]⁺, RT 3.3 min.

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7 Hz), 1.29 (m, 2H), 1.61 (m, 2H), 2.22 (m, 2H), 3.89 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7 Hz), 4.17 (s, 2H), 4.67 (t, 2H, J=7 Hz), 7.20-7.32 (m, 5H), 14.5 (br s, 1H).

Example 36 8-Chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione

5-[(4-Fluorophenyl)methyl]-1H-tetrazole (75 mg, 0.4 mmol) was treated with potassium carbonate (100 mg, 0.7 mmol) and DMF (3 ml). The mixture was treated with a solution of 3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (100 mg, 0.2 mmol) in DMF (0.5 ml). The mixture was stirred and heated at 60° C. 3 hours then cooled and evaporated. The residue was partitioned between chloroform (4 ml) and water (2 cm³). 1 cm³ of saturated aqueous sodium bicarbonate (3 ml) was added to each. The mixture was separated and the organic phase evaporated. The residue was dissolved in anhydrous THF (3 ml) and the mixture degassed by the cautious successive application of vacuum and nitrogen pressure to the mixture. The mixture was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) and morpholine (0.2 ml, 2.3 mmol) and then stirred in a nitrogen atmosphere for 2 h. The mixture was evaporated and partitioned between chloroform (4 ml) and saturated aqueous ammonium chloride (3 ml). The mixture was separated, and the aqueous phase re-extracted with chloroform. The organic phase was evaporated and the residue dissolved in MeOH (3 ml). The solution was added to the top of a 2 g aminopropyl SPE and washed with MeOH (15 ml). The desired product was eluted from the cartridge with a 3% v/v solution of AcOH in MeOH (20 ml). Product containing fractions were combined and evaporated and the residue subjected to purification by flash column chromatography (gradient elution from 10:1 cyclohexane/EtOAc to EtOAc). Product-containing fractions were combined and evaporated to yield the product as a colourless oil. Trituration in minimal diethyl ether caused the product to solidify and this was thoroughly dried to yield the title compound as a white solid (18.7 mg, 18%).

LC/MS: m/z 515 [MH]⁺, RT 3.31 min.

¹H NMR (CDCl₃) δ: 2.06 (m, 2H), 2.21 (m, 2H), 2.45 (m, 2H), 4.17 (m, 4H), 4.24 (t, 2H, J=7.0 Hz), 4.70 (t, 2H, J=7.2 Hz), 6.96 (m, 2H), 7.25 (m, 2H).

b) 3-[8-Chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate

A solution of 8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (0.82 g, 2.1 mmol) in DCM (20 ml) was treated with triethylamine (0.42 ml, 3.1 mmol) and methanesulfonic anhydride (0.40 g, 2.3 mmol). After 1 h the mixture was treated with saturated aqueous sodium bicarbonate (20 ml). The mixture was separated and the organic phase dried (MgSO₄), filtered and evaporated to give the title compound (0.91 g), which was used without further purification.

LC/MS: m/z 473 [MH]⁺, RT 3.17 min.

c) 8-Chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (1.0 g, 3.0 mmol) in DMF (15 ml) was treated with caesium carbonate (1.16 g, 3.6 mmol) and 3-bromo-1-propanol (0.3 ml, 3.3 mmol). The mixture was heated at 60° C. for 4 h and then cooled and evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was dried (MgSO₄), filtered and evaporated. The product was purified by flash chromatography using a gradient elution from cyclohexane to EtOAc. Product-containing fractions were combined and evaporated to give the title compound as a colourless oil (0.82 g, 75%).

LC/MS: m/z 395 [MH]⁺, RT 2.90 min.

d) 8-Chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 8.8 mmol) in DMF (20 ml) was treated with sodium carbonate (1.15 g, 10.8 mmol) and 4-bromo-1,1,1-trifluorobutane (1.86 g, 9.7 mmol). The mixture was stirred at 50° C. for 18 h then cooled and evaporated. The residue was partitioned between EtOAc (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase was dried (MgSO₄), filtered and evaporated. The residue was triturated in a mixture of diethyl ether and cyclohexane then the product filtered off and dried to yield the title compound as a white solid (1.18 g, 40%).

LC/MS: m/z 337 [MH]⁺, RT 2.83 min.

e) 5-[(4-Fluorophenyl)methyl]-1H-tetrazole

A mixture of triethylammonium chloride (4.14 g, 30 mmol) and sodium azide (1.95 g, 30 mmol) was treated with a solution of (4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) in toluene (14 ml) and the mixture was stirred and heated at 100° C. for 5 h. The cooled mixture was treated with water (10 ml) and the mixture separated. The aqueous phase was stirred and treated dropwise with concentrated hydrochloric acid until the product had precipitated from solution. The precipitated product was filtered off, washed with water and dried to yield the title compound as a white solid (1.27 g, 72%).

LC/MS: m/z 179 [MH]⁺, RT 2.24 min.

The compounds in Table 3 were prepared using a method analogous to that for Example 36: 8-chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione, with the appropriate methanesulfonate and tetrazole. MDAP was employed to further purify those compounds insufficiently pure following normal phase chromatography.

Methanesulfonates intermediates and their precursor alcohols were prepared according to the following procedures:

3-[8-Chloro-2,6-dioxo-7-(2-propen-1-yl)-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate

A solution of 8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (1.99 g, 6.1 mmol) in DCM (50 ml) was treated with triethylamine (1.2 ml, 8.6 mmol) and methanesulfonic anhydride (1.2 g, 6.9 mmol). After 1.5 h the mixture was treated with water (50 ml). The mixture was separated and the aqueous phase extracted with DCM (25 ml), the combined organic phases dried (MgSO₄), filtered and evaporated to give the title compound as a pale yellow oil (2.38 g), which was used without further purification.

LC/MS: m/z 405 [MH]⁺, RT 2.93 min.

3-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate

Prepared according to the method used for 3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate to give the title compound as a pale yellow oil (2.44 g).

LC/MS: m/z 419 [MH]⁺, RT 3.14 min.

8-Chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (3.0 g, 11.1 mmol) in DMF (20 ml) was treated with caesium carbonate (3.7 g, 11.4 mmol) and 3-bromo-1-propanol (1.6 g, 11.5 mmol). The mixture was heated at 60° C. for 4 h and then cooled and evaporated. The residue was partitioned between EtOAc (60 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous phase was extracted with EtOAc (60 ml), the combined organic phases were dried (MgSO₄), filtered and evaporated. The product was purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a colourless oil (2.6 g).

LC/MS: m/z 327 [MH]⁺, RT 2.62 min.

3-Butyl-8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

Prepared according to the method used for 8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione to give the title compound as a colourless oil (2.3 g).

LC/MS: m/z 341 [MH]⁺, RT 2.85 min.

TABLE 3 # Structure Name Yield LC/MS: 37

8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 12.4 mg (14%) m/z 447 [MH]⁺ RT 3.14 min 38

8-chloro-3-propyl-1-[3-(5-{[3- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 8.0 mg (8%) m/z 497 [MH]⁺ RT 3.36 min 39

8-chloro-3-(4,4,4-trifluorobutyl)-1-[3- (5-{[3- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 21.0 mg (19%) m/z 565 [MH]⁺ RT 3.34 min 40

8-chloro-3-(4,4,4-trifluorobutyl)-1-(3- {-5-[(2,4,6-trifluorophenyl)methyl]- 2H-tetrazol-2-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 17.0 mg (15%) m/z 551 [MH]⁺ RT 3.27 min 41

8-chloro-1-(3-{5-[(3,4- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-(4,4,4-trifluorobutyl)- 3,7-dihydro-1H-purine-2,6-dione 19.1 mg (18%) m/z 533 [MH]⁺ RT 3.36 min 42

3-butyl-8-chloro-1-[3-(5-{[2-fluoro-5- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 23.9 mg (23%) m/z 529 [MH]⁺ RT 3.50 min 43

8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3-(4,4,4-trifluorobutyl)- 3,7-dihydro-1H-purine-2,6-dione 19.8 mg (19%) m/z 515 [MH]⁺ RT 3.31 min 44

8-chloro-1-(3-{5-[(2,6- dichlorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 50.7 mg (51%) m/z 497 [MH]⁺ RT 3.33 min 45

3-butyl-8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 46.4 mg (48%) m/z 461 [MH]⁺ RT 3.27 min 46

3-butyl-8-chloro-1-(3-{5-[(2- chlorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 25.4 mg (27%) m/z 477 [MH]⁺ RT 3.40 min 47

3-butyl-8-chloro-1-(3-{5-[(3- fluorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 36.8 mg (40%) m/z 461 [MH]⁺ RT 3.31 min 48

3-butyl-8-chloro-1-(3-{5-[(3- chlorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 38.5 mg (40%) m/z 477 [MH]⁺ RT 3.45 min 49

3-butyl-8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 31.6 mg (34%) m/z 461 [MH]⁺ RT 3.31 min 50

3-butyl-8-chloro-1-(3-{5-[(4- chlorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 33.1 mg (35%) m/z 477 [MH]⁺ RT 3.46 min 51

3-butyl-8-chloro-1-(3-{5-[(2- methylphenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 39.5 mg (43%) m/z 457 [MH]⁺ RT 3.37 min 52

3-butyl-8-chloro-1-(3-{5-[(3- methylphenyl)methyl]-2H-tetrazol-2- yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 36.5 mg (40%) m/z 457 [MH]⁺ RT 3.40 min 53

3-butyl-8-chloro-1-[3-(5-{[3- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 43.7 mg (43%) m/z 511 [MH]⁺ RT 3.50 min 54

3-butyl-8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 28.6 mg (30%) m/z 473 [MH]⁺ RT 3.29 min 55

3-butyl-8-chloro-1-{3-[5-(1- phenylcyclopropyl)-2H-tetrazol-2- yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 44.2 mg (47%) m/z 469 [MH]⁺ RT 3.41 min 56

3-butyl-8-chloro-1-{3-[5-(2- phenylethyl)-2H-tetrazol-2- yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 39.2 mg (43%) m/z 457 [MH]⁺ RT 3.36 min 57

3-butyl-8-chloro-1-{3-[5-(2- thienylmethyl)-2H-tetrazol-2- yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 33.4 mg (37%) m/z 449 [MH]⁺ RT 3.20 min 58

3-butyl-8-chloro-1-(3-{5-[(2,6- dichlorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 36.4 mg (36%) m/z 511 [MH]⁺ RT 3.49 min 59

8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 5.6 mg (6%) m/z 447 [MH]⁺ RT 3.10 min 60

8-chloro-1-(3-{5-[(3- chlorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 5.9 mg (6%) m/z 463 [MH]⁺ RT 3.29 min 61

8-chloro-1-(3-{5-[(4- chlorophenyl)methyl]-2H-tetrazol-2- yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 14.9 mg (16%) m/z 463 [MH]⁺ RT 3.30 min 62

8-chloro-1-(3-{5-[(3- methylphenyl)methyl]-2H-tetrazol-2- yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 17.5 mg (20%) m/z 443 [MH]⁺ RT 3.23 min 63

8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione 14.5 mg (16%) m/z 459 [MH]⁺ RT 3.12 min 64

8-chloro-3-propyl-1-{3-[5-(2- thienylmethyl)-2H-tetrazol-2- yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 17.0 mg (20%) m/z 435 [MH]⁺ RT 3.02 min 65

8-chloro-1-(3-{5-[(2,6- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-propyl-3,7-dihydro- 1H-pyrine-2,6-dione 18.4 mg (20%) m/z 465 [MH]⁺ RT 3.11 min 66

8-chloro-1-(3-{5-[(3,4- dichlorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 19.4 mg (20%) m/z 497 [MH]⁺ RT 3.44 min 67

8-chloro-1-(3-{5-[(2,4- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 19.1 mg (21%) m/z 465 [MH]⁺ RT 3.16 min 68

8-chloro-1-(3-{5-[(3,4- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 21.5 mg (23%) m/z 465 [MH]⁺ RT 3.19 min 69

8-chloro-1-(3-{5-[(2,5- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 8.5 mg (9%) m/z 465 [MH]⁺ RT 3.14 min 70

8-chloro-3-propyl-1-(3-{5-[(2,4,6- trifluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 17.4 mg (18%) m/z 483 [MH]⁺ RT 3.09 min 71

8-chloro-1-[3-(5-{[2-fluoro-6- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione 22.3 mg (22%) m/z 515 [MH]⁺ RT 3.28 min 72

8-chloro-1-[3-(5-([4-fluoro-3- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione 17.2 mg (17%) m/z 515 [MH]⁺ RT 3.30 min 73

8-chloro-1-[3-(5-{[2-fluoro-5- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione 18.2 mg (18%) m/z 515 [MH]⁺ RT 3.34 min 74

3-butyl-8-chloro-1-(3-{5-[(2,6- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 18.2 mg (19%) m/z 479 [MH]⁺ RT 3.29 min 75

3-butyl-8-chloro-1-(3-{5-[(3,4- dichlorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 20.1 mg (20%) m/z 511 [MH]⁺ RT 3.58 min 76

3-butyl-8-chloro-1-(3-{5-[(2,4- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 19.3 mg (20%) m/z 479 [MH]⁺ RT 3.33 min 77

3-butyl-8-chloro-1-(3-{5-[(2-chloro- 6-fluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 18.9 mg (19%) m/z 495 [MH]⁺ RT 3.33 min 78

3-butyl-8-chloro-1-(3-{5-[(3,4- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 21.7 mg (23%) m/z 479 [MH]⁺ RT 3.33 min 79

3-butyl-8-chloro-1-[3-(5-{[2- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 18.1 mg (18%) m/z 511 [MH]⁺ RT 3.32 min 80

3-butyl-8-chloro-1-(3-{5-[(2,5- difluorophenyl)methyl]-2H-tetrazol- 2-yl)propyl)-3,7-dihydro-1H-purine- 2,6-dione 24.0 mg (25%) m/z 479 [MH]⁺ RT 3.31 min 81

3-butyl-8-chloro-1-(3-{5-[(3,5- difluorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 15.9 mg (17%) m/z 479 [MH]⁺ RT 3.38 min 82

3-butyl-8-chloro-1-{3-[5-({2- [(trifluoromethyl)oxy]phenyl}methyl)- 2H-tetrazol-2-yl]propyl}-3,7-dihydro- 1H-purine-2,6-dione 32.8 mg (31%) m/z 527 [MH]⁺ RT 3.51 min 83

3-butyl-8-chloro-1-(3-{5-[(2,4,6- trifluorophenyl)methyl]-2H-tetrazol- 2-yl)propyl)-3,7-dihydro-1H-purine- 2,6-dione 20.7 mg (21%) m/z 497 [MH]⁺ RT 3.35 min 84

3-butyl-8-chloro-1-[3-(5-{[2-fluoro-6- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 23.9 mg (23%) m/z 529 [MH]⁺ RT 3.44 min 85

3-butyl-8-chloro-1-[3-(5-{[4-fluoro-3- (trifluoromethyl)phenyl]methyl}-2H- tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 13.9 mg (13%) m/z 529 [MH]⁺ RT 3.53 min 86

3-butyl-8-chloro-1-(3-{5-[(2,4- dichlorophenyl)methyl]-2H-tetrazol- 2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 17.5 mg (17%) m/z 511 [MH]⁺ RT 3.63 min NMR Details for Selected Examples from Table 3:

Example 37 8-Chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.99 (t, 3H, J=7.5 Hz), 1.80 (m, 2H), 2.46 (m, 2H), 4.06 (m, 2H), 4.18 (s, 2H), 4.25 (t, 2H, J=7 Hz), 4.70 (t, 2H, J=7.5 Hz), 6.96 (m, 2H), 7.26 (m, 2H), 13.15 (br s, 1H).

Example 40 8-Chloro-3-(4,4,4-trifluorobutyl)-1-(3-{5-[(2,4,6-trifluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 2.07 (m, 2H), 2.21 (m, 2H), 2.44 (m, 2H), 4.18 (t, 2H, J=7.1 Hz), 4.20 (s, 2H), 4.24, (t, 2H, J=6.8 Hz), 4.68 (t, 2H, J=7.3 Hz), 6.67 (t, 2H, J=8.1 Hz), 13.04 (br s, 1H).

Example 41

¹H NMR (CDCl₃): 2.03-2.10 (m, 2H), 2.16-2.28 (m, 2H), 2.43-2.50 (m, 2H), 4.16-4.19 (m, 2H), 4.17 (s, 2H), 4.24 (t, 2H, J=7.1 Hz), 4.71 (t, 2H, J=7.1 Hz), 7.00-7.13 (m, 3H), 13.06 (bs, 1H).

Example 44

¹H NMR (CDCl₃): 0.99 (t, 3H, J=7.5 Hz), 1.76-1.86 (m, 2H), 2.40-2.47 (m, 2H), 4.05-4.09 (m, 2H), 4.23-4.26 (m, 2H), 4.54 (s, 2H), 4.65-4.69 (m, 2H), 7.14-7.18 (m, 1H), 7.31-7.33, (m, 2H), 13.18 (bs, 1H).

Example 45

¹H NMR (CDCl₃): 0.97 (t, 3H, J=7.5 Hz), 1.36-1.46 (m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.08-4.11 (m, 2H), 4.25 (s, 2H), 4.24-4.27 (m, 2H), 4.68-4.71 (m, 2H), 7.02-7.09 (m, 2H), 7.20-7.26, (m, 2H), 13.14 (bs, 1H).

Example 46

¹H NMR (CDCl₃): 0.97 (t, 3H, J=7.5 Hz), 1.36-1.45 (m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.09 (t, 2H, J=7.5 Hz), 4.26 (t, 2H, J=7.5 Hz), 4.34 (s, 2H), 4.70 (t, 2H, J=7.3 Hz), 7.18-7.21 (m, 2H), 7.25-7.27, (m, 1H), 7.35-7.37, (m, 1H), 13.34 (bs, 1H).

Example 47 3-Butyl-8-chloro-1-(3-{5-[(3-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.97 (t, 3H, J=7 Hz), 1.40 (m, 2H), 1.75 (m, 2H), 2.46 (m, 2H), 4.10 (t, 2H, J=7.5 Hz), 4.21 (s, 2H), 4.26 (t, 2H , J=6.5 Hz), 4.70 (t, 2H, J=7.5 Hz), 6.90 (m, 1H), 6.99 (m, 1H), 7.07 (m, 1H), 7.25 (m, 1H), 13.25 (br s, 1H).

Example 48

¹H NMR (CDCl₃): 0.99 (t, 3H, J=7.5 Hz), 1.38-1.48 (m, 2H), 1.73-1.81 (m, 2H), 2.44-2.51 (m, 2H), 4.12 (t, 2H, J=7.5 Hz), 4.20 (s, 2H), 4.27 (t, 2H, J=7.5 Hz), 4.70 (t, 2H, J=7.3 Hz), 6.95-7.00 (m, 2H), 7.26-7.30, (m, 2H), 13.35 (bs, 1H).

Example 49 3-Butyl-8-chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.99 (t, 3H, J=7 Hz), 1.43 (m, 2H), 1.77 (m, 2H), 2.48 (m, 2H), 4.12 (t, 2H, J=7.5 Hz), 4.20 (s, 2H), 4.27 (t, 2H, J=7 Hz), 4.72 (t, 2H, J=7.5 Hz), 6.98 (m, 2H), 7.27 (m, 2H), 13.35 (br s, 1H).

Example 50 3-Butyl-8-chloro-1-(3-{5-[(4-chlorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3,7-dihydro-1H-purine-2,6-d lone

¹H NMR (CDCl₃) δ: 1.02 (t, 3H, J=7.5 Hz), 1.45 (m, 2H), 1.79 (m, 2H), 2.50 (m, 2H), 4.14 (t, 2H, J=7.5 Hz), 4.22 (s, 2H), 4.29 (t, 2H, J=7 Hz), 4.75 (t, 2H, J=7.5 Hz), 7.27 (s, 4H), 13.35 (br s, 1H).

Example 55 3-Butyl-8-chloro-1-{3-[5-(1-phenylcyclopropyl)-2H-tetrazol-2-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.93 (t, 3H, J=7.3 Hz), 1.36 (m, 4H), 1.55 (m, 2H), 1.71 (m, 2H), 2.38 (m, 2H), 4.06 (t, 2H, J=7.5 Hz), 4.20 (t, 2H, J=6.7 Hz), 4.59 (t, 2H, J=7.5 Hz), 7.25 (m, 3H), 7.36 (m, 2H), 13.30 (br s, 1H).

Example 67 8-Chloro-1-(3-{5-[(2,4-difluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.99 (t, 3H, J=7.5 Hz), 1.80 (m, 2H), 2.45 (m, 2H), 4.06 (m, 2H), 4.20 (s, 2H), 4.25 (t, 2H, J=7 Hz), 4.70 (t, 2H, J=7.5 Hz), 6.80 (m, 2H), 7.23 (m, 1H).

Example 70 8-Chloro-3-propyl-1-(3-(5-[(2,4,6-trifluorophenyl)methyl]-2H-tetrazol-2-yl)propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.99 (t, 3H, J=7.3 Hz), 1.80 (m, 2H), 1.98 (m, 2H), 2.01 (m, 2H), 4.20 (s, 2H), 4.25 (t, 2H, J=6.5 Hz), 4.67 (t, 2H, J=7.3 Hz), 6.68 (t, 2H, J=8.1 Hz).

Example 71

¹H NMR (CDCl₃): 0.99 (t, 3H, J=7.3 Hz), 1.76-1.85 (m, 2H), 2.39-2.46 (m, 2H), 4.05-4.08 (m, 2H), 4.24 (t, 2H, J=7.1 Hz), 4.39 (s, 2H), 4.64 (t, 2H, J=7.1 Hz), 7.29-7.32 (m, 1H), 7.38-7.44, (m, 1H), 7.49-7.51, (m, 1H), 13.17 (bs, 1H).

Example 78

¹H NMR (CDCl₃): 0.99 (t, 3H, J=7.6 Hz), 1.36-1.45 (m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.09 (t, 2H, J=7.5 Hz), 4.17 (s, 2H), 4.24 (t, 2H, J=7.5 Hz), 4.71 (t, 2H, J=7.3 Hz), 7.00-7.14 (m, 3H), 13.07 (bs, 1H).

Example 80

¹H NMR (CDCl₃): 0.96 (t, 3H, J=7.2 Hz), 1.32-1.47 (m, 2H), 1.68-1.80 (m, 2H), 2.40-2.51 (m, 2H), 4.06-4.12 (m, 2H), 4.22 (s, 2H), 4.22-4.27 (m, 2H), 4.67-4.73 (m, 2H), 6.84-7.04 (m, 3H), 13.05 (bs, 1H).

Example 83 3-Butyl-8-chloro-1-(3-{5-[(2,4,6-trifluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (CDCl₃) δ: 0.97 (t, 3H, J=7.3 Hz), 1.41 (m, 2H), 1.75 (m, 2H), 2.44 (m, 2H), 4.10 (t, 2H, J=7.5 Hz), 4.20 (s, 21-1), 4.25 (t, 2H, J=6.5 Hz), 4.67 (t, 2H, J=7.4 Hz), 6.67 (t, 2H, J=8.0 Hz), 13.25 (br s, 1H).

Example 87 8-Chloro-3-pentyl-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-1-(3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (88 mg, 0.4 mmol) in THF (4 ml) was treated with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.34 mmol) and PPh₃ (115 mg, 0.44 mmol) under nitrogen. DBAD (101 mg, 0.44 mmol) was added in one portion and the reaction left to react for 5 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (39 mg, 0.034 mmol) was added and the mixture degassed once more. Morpholine (294 μl, 3.4 mmol) was added and the mixture was stirred under nitrogen for 3 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The title compound was obtained as a white solid after purification by MDAP (64 mg, 42%).

LC/MS: m/z 457 [MH]⁺, RT 3.4 min.

¹H NMR (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz), 1.22-1.34 (m, 4H), 1.62 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7 Hz), 3.88 (t, 2H, J=7 Hz), 3.95-4.00 (m, 4H), 7.22-7.33 (m, 5H), 14.5 (br s, 1H).

b) 3-[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol

A mixture of γ-butyrolactone (223 μl, 2.9 mmol), benzamidine oxime (480 mg, 3.2 mmol), 21% solution of NaOEt in EtOH (1.3 ml) and EtOH (3 ml) was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The title product was purified over silica using the Companion™ system to give a pale yellow oil (143 mg, 23%).

LC/MS: m/z 219 [MH]⁺, RT 2.4 min.

Example 88 8-Chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g, 0.34 mmol) in DMF (5 ml) was degassed by sequential evacuation of the flask and admission of nitrogen (×3) and morpholine (0.5 ml, 5.8 mmol), and Pd(PPh₃)₄ (80 mg, 0.068 mmol) added. The solution was stirred for 72 h then concentrated and the residues loaded onto an aminopropyl SPE (10 g) with MeOH. Elution with MeOH followed by 5% AcOH/MeOH provided the title compound as a pale yellow solid, which was washed with ether to yield a white solid (0.053 g, 32%).

LC/MS: m/z 491 [MH]⁺, RT 3.69 min

b) 8-Chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

i) A mixture of γ-butyrolactone (8 ml, 104 mmol), 4-chlorobenzamidine oxime (3.0 g, 16.25 mmol), 30% solution of NaOMe in MeOH (5 ml) and MeOH (80 ml) was refluxed for 30 h, cooled and concentrated. The residues were purified by flash chromatography over silica eluting with DCM/EtOH/0.88 aq ammonia (200:8:1) to provide a yellow oil (13 g). This material was dissolved in DCM (150 ml) and washed with 2M sodium hydroxide (100 ml) and the organics separated, dried and concentrated to yield 3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-1-propanol as a viscous oil (3.95 g, 96%) which was used in the next step.

ii) To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.10 g, 0.34 mmol), 3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-1-propanol (0.086 g, 0.34 mmol) and triphenylphosphine (0.186 g, 0.69 mmol) in THF (5 ml) was added dibenzylazodicarboxylate (0.204 g, 0.68 mmol) and the solution stirred for 18 h. The solution was then concentrated and the residues chromatographed over silica (20 g, SPE) eluting with DCM initially then DCM/Et₂O mixtures to yield the title compound contaminated with dibenzylazodicarboxylate by-products (0.18 g). Material used crude in deprotection step.

LC/MS: m/z 531 [MH]⁺, RT 3.83 min.

Example 89 8-Chloro-3-pentyl-1-{3-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-1-{3-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (150 mg, 0.65 mmol) in THF (6 ml) was treated with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (160 mg, 0.54 mmol) and PPh₃ (183 mg, 0.70 mmol) under nitrogen. DBAD (161 mg, 0.70 mmol) was added in one portion and the reaction left to react for 18 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (39 mg, 0.034 mmol) was added and the mixture degassed once more. Morpholine (294 μl, 3.4 mmol) was added and the mixture was stirred under nitrogen for 3 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The residue was taken up into MeOH and purified by passing down an aminopropyl SPE, the product eluted with 2-5% AcOH/MeOH. The title compound was obtained as an off-white solid (185 mg, 73%).

LC/MS: m/z 471 [MH]⁺, RT 3.6 min.

¹H NMR; (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz), 1.23-1.34 (m, 4H), 1.63 (m, 2H), 2.06 (m, 2H), 2.87 (m, 4H), 2.93 (t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 4.00 (t, 2H, J=6.5 Hz), 7.16-7.29 (m, 5H), 14.5 (br s, 1H).

b) 3-[3-(2-Phenylethyl)-1,2,4-oxadiazol-5-yl]-1-propanol

A mixture of γ-butyrolactone (426 μl, 5.5 mmol), phenethylamidine oxime (1.0 g, 6.1 mmol), 21% solution of NaOEt in EtOH (2 ml) and EtOH (3 ml) was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The title product was purified by Si-SPE eluting with EtOAc/cyclohexane mixtures to give the title compound as a pale yellow oil (390 mg, 31%).

LC/MS: m/z 233 [MH]⁺, RT 2.5 min.

Example 90 8-Chloro-1-{3-[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-propyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-propyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (195 mg, 0.89 mmol) and PPh₃ (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The crude product was purified by a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated and further purified by a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh₃)₄ (86 mg, 0.074 mmol) and morpholine (644 μl, 7.4 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (74 mg, 23%).

LC/MS: m/z 429 [MH]⁺, RT 3.14 min.

¹H NMR; (DMSO-d₆) δ: 0.87 (t, 3H, J=7.5 Hz), 1.65 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 3.86 (t, 2H, J=7 Hz), 3.97 (s,t overlapping, 4H), 7.27 (m, 5H) 14.46 (s, 1H).

b) 8-Chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione

A mixture of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.6 mmol), 1-iodopropane (1.2 g, 6.9 mmol) and sodium carbonate (0.9 g, 8.5 mmol) in DMF (40 ml) was heated at 50° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue treated with water (60 ml) and extracted with EtOAc (3×80 ml). The combined organic extracts were dried (MgSO₄) filtered and evaporated. The residue was triturated with ether/cyclohexane, the solid was filtered off and dried to afford the title compound (0.82 g, 46%).

LC/MS: m/z 269 [MH]⁺.

Example 91 8-Chloro-3-pentyl-1-{3-[3-(3-thienylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-1-{3-[3-(3-thienylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A mixture of ethyl 4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (70 mg, 0.19 mmol), N-hydroxy-2-(3-thienyl)ethanimidamide (36 mg, 0.23 mmol), 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated and purified by MDAP. The title compound was freeze dried from 1,4-dioxane to give a white solid (27 mg, 31%).

LC/MS: m/z 463 [MH]⁺, RT 3.4 min.

b) Ethyl 4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate

A solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.0 g, 10.1 mmol) in anhydrous DMF (35 ml) was treated with Cs₂CO₃ (3.6 g, 11.1 mmol) and ethyl 4-bromobutyrate (1.6 ml, 11.1 mmol). The mixture was stirred at rt for 18 h then degassed under a gentle vacuum, then nitrogen introduced. This was repeated twice. Pd(PPh₃)₄ (1.17 g, 1.0 mmol) was added and the mixture degassed once more. Morpholine (8.8 ml, 101 mmol) was added and left to stir for 3 h at rt. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow solid (5.16 g). The residue was taken up in MeOH and divided into two equal portions, and then each passed down an aminopropyl SPE (20 g), eluting with MeOH followed by 5% AcOH/MeOH. The product fractions were combined and concentrated giving the title compound as a near white solid (3.01 g, 80%).

LC/MS: m/z 371 [MH]⁺, RT 3.2 min.

Example 92 8-Chloro-3-pentyl-1-{3-[3-(1-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A mixture of ethyl 4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (70 mg, 0.19 mmol), N-hydroxy-2-phenylpropanimidamide (38 mg, 0.23 mmol), 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated and purified by the MDAP. The title compound was freeze dried from 1,4-dioxane to give a white solid (44 mg, 49%).

LC/MS: m/z 471 [MH]⁺, RT 3.6 min.

Example 93 3-Butyl-8-chloro-1-{3-[3-(2,3-difluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{3-[3-(2,3-difluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

2,3-Difluorophenylacetonitrile (23 mg, 0.15 mmol) was dissolved in EtOH (1 ml). Hydroxylamine hydrochloride (14 mg, 0.20 mmol) was added, followed by water (0.5 ml) and potassium carbonate (41 mg, 0.3 mmol). The mixture was heated at reflux overnight and then cooled and partitioned between EtOAc and brine. The organic phase was evaporated and the crude amidoxime thus obtained was dissolved in EtOH (1 ml). Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (43 mg, 0.12 mmol) and 21% by wt. ethanolic sodium ethoxide ((0.067 ml, 0.18 mmol) was added and the mixture heated in the microwave reactor at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl, the organic phase evaporated and the product purified by MDAP to provide the title compound as a solid (13 mg).

LC/MS: m/z 479 [MH]⁺, RT 3.52 min.

¹H NMR (MeOH-d₄) δ: 0.96 (t, 3H, J=7 Hz), 1.34-1.45 (m, 2H), 1.65-1.75 (m, 2H), 2.13-2.22 (m, 2H), 2.97 (t, 2H, J=7 Hz), 4.00 (t, 2H, J=7 Hz), 4.05 (s, 2H), 4.12 (t, 2H, J=7 Hz), 7.03-7.25 (m, 3H).

b) Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate

To 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (6.0 g, 21.24 mmol) in dry DMF (100 ml) was added Cs₂CO₃ (7.62 g, 23.36 mmol) followed by ethyl 4-bromobutyrate (4.556 g, 23.36 mmol). The mixture was heated at 55° C. for 18 h and allowed to cool then degassed by repeatedly evacuating and readmitting nitrogen. Morpholine (14.9 g, 171 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (4.0 g, 3.46 mmol) and the mixture was stirred for 4 h. EtOAc (300 ml) and 2M HCl (150 ml) and water (100 ml) were added and the organic phase separated, washed with brine (3×100 ml) and filtered. The filtrate was dried (Na₂SO₄) and evaporated. The crude product (10 g) was purified by aminopropyl SPE (3×20 g), loading in THF/MeOH (1:1), washing with THF/MeOH (1:1) and neat MeOH and eluting the product with DCM/MeOH (1:1) containing 5% added AcOH to afford the title compound (5.08 g).

LC/MS: m/z 357 [MH]⁺, RT 3.06 min.

¹H NMR (d⁴ MeOH) 0.96 (3H, t, J=7 Hz), 1.33-1.42 (2H, m), 1.64-1.74 (2H, m), 2.12-2.21 (2H, m), 2.95 (2H, t, J=8 Hz), 3.99 (2H, t, J=7 Hz), 4.03 (2H, s), 4.11 (2H, t, J=7 Hz), 7.03-7.21 (3H, m).

Example 94 3-Butyl-8-chloro-1-{3-[3-(2-chlorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-(2-chlorophenyl)-N-hydroxyethanimidamide (30 mg, 0.18 mmol; Entry 1, table 7) were heated in EtOH (0.75 ml) with 21% ethanolic sodium ethoxide (0.083 ml, 0.22 mmol) at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase evaporated. The product was purified by MDAP to yield the title compound as a solid (34.8 mg).

LC/MS: m/z 477 [MH]⁺, RT 3.59 min.

¹H NMR (d⁶ DMSO) 0.89 (3H, t, J=8 Hz), 1.24-1.34 (2H, m), 1.56-1.65 (2H, m), 1.98-2.07 (2H, m), 2.92 (2H, t, J=7 Hz), 3.89 (2H, t, J=7 Hz), 3.98 (2H, t, J=7 Hz), 4.09 (2H, s), 7.28-7.48 (4H, m).

Example 95 3-Butyl-8-chloro-1-{3-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

Starting from (1Z)-2-(4-fluorophenyl)-N-hydroxyethanimidamide (28 mg, 0.18 mmol; Entry 2, Table 7) was similarly obtained the title compound as a solid (10.0 mg).

LC/MS: m/z 461 [MH]⁺, RT 3.49 min.

Example 96 3-Butyl-8-chloro-1-{3-[3-(2,3-dichlorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-(2,3-dichlorophenyl)-N-hydroxyethanimidamide (36 mg, 0.165 mmol; Entry 3, Table 7) and 21% ethanolic sodium ethoxide (0.083 ml, 0.22 mmol) were heated together in EtOH (0.75 ml) in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl, the organic phase separated, evaporated and the product purified by MDAP to give the title compound as a solid (42.1 mg).

LC/MS: m/z 511, 513, 515 (isotopes) [MH]⁺, RT 3.66 min.

The following compounds (Table 4) were prepared using a method analogous to that for Example 96, using the appropriate amidoxime, (with the exceptions that for Example 110 (Table 4) during workup the pH was adjusted to 5 prior to extraction with EtOAc; and in the case of Example 111 (Table 4) the crude product was stirred for 18 h with EtOH (1 ml) and 2M NaOH (0.5 ml) and Example 112 (Table 4) was stirred for 18 h with EtOH (0.75 ml) and 2M NaOH (0.5 ml) prior to repeat workup and purification by MDAP).

TABLE 4 Amidoxime Wt of (see table amidoxime Yield Example Structure 7) Mg mg LC/MS: 97

4 28 32.4 m/z 461 [MH]⁺ RT 3.41 min 3-butyl-8-chloro-1-{3-[3-(3- fluorobenzyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 98

5 31 28.3 m/z 479 [MH]⁺ RT 3.46 min 3-butyl-8-chloro-1-{3-[3-(3,4- difluorobenzyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 99

6 33 32.3 m/z 495 [MH]⁺ RT 3.55 min 3-butyl-8-chloro-1-{3-[3-(3-chloro-2- fluorobenzyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 100

8 29 35 m/z 469 [MH]⁺ RT 3.43 min 3-butyl-8-chloro-1-{3-[3-(1- phenylcyclopropyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 101

9 42 2.6 m/z 551 [MH]⁺ RT 3.71 min 1-(3-{3-[1-(3-bromophenyl)-1- methylethyl]-1,2,4-oxadiazol-5- yl}propyl)-3-butyl-8-chloro-3,7-dihydro- 1H-purine-2,6-dione 102

10 32 30.5 m/z 487 [MH]⁺ RT 3.27 min 1-{3-[3-(1,3-benzodioxol-5-ylmethyl)- 1,2,4-oxadiazol-5-yl]propyl}-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6-dione 103

19 33 26.2 m/z 495 [MH]⁺ RT 3.47 min 3-butyl-8-chloro-1-(3-{3-[(2-chloro-5- fluorophenyl)methyl]-1,2,4-oxadiazol- 5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 104

21 26 33.4 m/z 449 [MH]⁺ RT 3.23 min 3-butyl-8-chloro-1-{3-[3-(2- thienylmethyl)-1,2,4-oxadiazol-5- yl]propyl)-3,7-dihydro-1H-purine-2,6- dione 105

22 31 27.3 m/z 483 [MH]⁺ RT 3.47 min 1-{3-[3-(1-benzofuran-3-ylmethyl)- 1,2,4-oxadiazol-5-yl]propyl}-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6-dione 106

15 42 29.8 m/z 545 [MH]⁺ RT 3.79 min 3-butyl-8-chloro-1-(3-{3-[(2,3,4- trichlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 107

16 31 34.8 m/z 479 [MH]⁺ RT 3.35 min 3-butyl-8-chloro-1-(3-{3-[(2,5- difluorophenyl)methyl]-1,2,4-oxadiazol- 5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 108

17 31 38.2 m/z 479 [MH]⁺ RT 3.31 min 3-butyl-8-chloro-1-(3-{3-[(2,6- difluorophenyl)methyl]-1,2,4-oxadiazol- 5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 109

18 31 35.4 m/z 479 [MH]⁺ RT 3.39 min 3-butyl-8-chloro-1-(3-{3-[(3,5- difluorophenyl)methyl]-1,2,4-oxadiazol- 5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 110

20 31 16.1 m/z 482 [MH]⁺ RT 3.31 min 3-butyl-8-chloro-1-{3-[3-(1H-indol-3- ylmethyl)-1,2,4-oxadiazol-5-yl]propyl}- 3,7-dihydro-1H-purine-2,6-dione 111

7 28 10 m/z 459 [MH]⁺ RT 3.07 min 3-butyl-8-chloro-1-(3-{3-[(3- hydroxyphenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 112

25 40 28.4 m/z 536 [MH]⁺ RT 3.03 min N-[3-({5-[3-(3-butyl-8-chloro-2,6-dioxo- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-1,2,4-oxadiazol-3- yl}methyl)phenyl]methanesulfanamide 113

(1S,2S)-N- hydroxy-2- phenylcyclo- propane- carboximid- amide 29 29.6 m/z 469 [MH]⁺ RT 3.51 min 3-butyl-8-chloro-1-(3-{3-[(1S,2S)-2- phenylcyclopropyl]-1,2,4-oxadiazol-5- yl}propyl)-3,7-dihydro-1H-purine-2,6- dione NMR Details for Selected Examples from Table 4:

Example 97 3-butyl-8-chloro-1-{3-[3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.25-1.36 (m, 2H), 1.56-1.67 (m, 2H), 2.0-2.1 (m, 2H), 2.94 (t, 2H, J=7 Hz), 3.90 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.02 (s, 2H), 7.05-7.15 (m, 3H), 7.32-7.40 (m, 1H).

Example 98 3-Butyl-8-chloro-1-{3-[3-(3,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7.5 Hz), 1.25-1.34 (m, 2H), 1.56-1.65 (m, 2H), 1.99-2.07 (m, 2H), 2.92 (t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.02 (s, 2H), 7.10-7.15 (m, 1H), 7.32-7.39 (m, 2H), 14.45 (br s, 1H).

Example 100 3-butyl-8-chloro-1-{3-[3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (MeOH-d₄) δ: 0.95 (t, 3H, J=7 Hz), 1.25-1.30 (m, 2H), 1.30-1.45 (m, 4H), 1.64-1.75 (m, 2H), 2.15-2.25 (m, 2H), 2.94 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.10 (t, 2H, J=7 Hz), 7.20-7.37 (m, 5H).

Example 102 1-{3-[3-(1,3-benzodioxol-5-ylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.25-1.36 (m, 2H), 1.58-1.68 (m, 2H), 1.98-2.09 (m, 2H), 2.92 (t, 2H, J=7 Hz), 3.88-3.95 (m, 4H), 3.99 (t, 2H, J=7 Hz), 5.98 (s, 2H), 6.70-6.86 (m, 3H).

Example 110 3-butyl-8-chloro-1-{3-[3-(1H-indol-3-ylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7 Hz), 1.23-1.36 (m, 2H), 1.56-1.67 (m, 2H), 1.96-2.08 (m, 2H), 2.90 (t, 2H, J=7 Hz), 3.90 (t, 2H, J=7 Hz), 3.99 (t, 2H, J=7 Hz), 4.04 (s, 2H), 6.92-7.50 (m, 5H), 10.95 (s, 1H).

Example 111 3-butyl-8-chloro-1-(3-{3-[(3-hydroxyphenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.25-1.38 (m, 2H), 1.57-1.68 (m, 2H), 1.96-2.07 (m, 2H), 2.92 (t, 2H, J=7 Hz), 3.86 (s, 2H), 3.89 (t, 2H, J=7 Hz), 3.99 (t, 2H, J=7 Hz), 6.58-6.68 (m, 3H), 7.08 (m, 1H), 9.40 (s, 1H).

Example 112 N-[3-({5-[3-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]-1,2,4-oxadiazol-3-yl}methyl)phenyl]methanesulfonamide

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7.5 Hz), 1.24-1.34 (m, 2H), 1.56-1.65 (m, 2H), 1.97-2.06 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 2.97 (s, 3H), 3.90 (t, 2H, J=7.5 Hz), 3.96 (s, 2H), 3.97 (t, 2H, J=7 Hz), 6.96-6.99 (m, 1H), 7.06-7.13 (m, 2H), 7.26 (t, 1H, J=8 Hz), 9.75 (s, 1H), 14.45 (br s, 1H).

Example 114 3-Butyl-8-chloro-1-(3-{3-[(3,4-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (71 mg, 0.2 mmol), (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (48 mg, 0.22 mmol) and 21% by wt. ethanolic sodium ethoxide (0.111 ml, 0.3 mmol) were heated together in EtOH (1 ml) in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated, and the crude product was purified by MDAP to give the title compound as a solid (48.8 mg).

LC/MS: m/z 511, 513 [MH]⁺, RT 3.65 min.

The following compounds (Table 5) were prepared using a method analogous to that for Example 114, using the appropriate amidoxime (with the exception that for Example 115 and Example 125, 0.185 ml, (0.5 mmol) of 21% sodium ethoxide was added in order to allow for the amidoximes being the hydrochloride salts).

TABLE 5 Wt of amidoxime Yield Example Structure Amidoxime mg mg LC/MS: 115

(1Z)-N- hydroxy-2-[3- (trifluoromethyl) phenyl] ethanimidamide hydrochloride 56 46.5 m/z 511 [MH]⁺ RT 3.63 min 3-butyl-8-chloro-1-[3-(3-{[3- (trifluoromethyl)phenyl]methyl}- 1,2,4-oxadiazol-5-yl)propyl]- 3,7-dihydro-1H-purine-2,6- dione 116

(1Z)-2-(2,6- dichlorophenyl)- N- hydroxy- ethanimidamide 48 53.8 m/z 511 [MH]⁺ RT 3.64 min 3-butyl-8-chloro-1-(3-{3-[(2,6- dichlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 117

(1Z)-N- hydroxy-2- phenyl- propanimidamide 36 45.4 m/z 457 [MH]⁺ RT 3.51 min 3-butyl-8-chloro-1-{3-[3-(1- phenylethyl)-1,2,4-oxadiazol- 5-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione 118

(1Z)-N- hydroxy-2-(1- naphthalenyl) ethanimidamide 44 48.6 m/z 493 [MH]⁺ RT 3.67 min 3-butyl-8-chloro-1-{3-[3-(1- naphthalenylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione 119

(1Z)-2-(4- chlorophenyl)- N- hydroxy- ethanimidamide 41 35.6 m/z 477 [MH]⁺ RT 3.60 min 3-butyl-8-chloro-1-(3-{3-[(4- chlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 120

(1Z)-N- hydroxy-3- phenyl- propanimidamide 36 29.6 m/z 457 [MH]⁺ RT 3.55 min 3-butyl-8-chloro-1-{3-[3-(2- phenylethyl)-1,2,4-oxadiazol- 5-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione 121

(1Z)-2-(3- chlorophenyl)- N- hydroxy- ethanimidamide 41 39.4 m/z 477 [MH]⁺ RT 3.64 min 3-butyl-8-chloro-1-(3-{3-[(3- chlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 122

(1Z)-N-hydroxy- 2-(4- hydroxyphenyl) ethanimidamide 36 53.5 m/z 459 [MH]⁺ RT 3.08 min 3-butyl-8-chloro-1-(3-{3-[(4- hydroxyphenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 123

(1Z)-N- hydroxy-2-[3- (trifluoromethyl)- 1H-pyrazol- 1- yl]ethanimidamide 46 58.1 m/z 501 [MH]⁺ RT 3.33 min 3-butyl-8-chloro-1-[3-(3-{[3- (trifluoromethyl)-1H-pyrazol- 1-yl]methyl}-1,2,4-oxadiazol- 5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 124

(1Z)-N- hydroxy-2-(3- thienyl) ethanimidamide 34 32.6 m/z 449 [MH]⁺ RT 3.31 min 3-butyl-8-chloro-1 -{3-[3-(3- thienylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione 125

(1Z)-2-(4- chlorophenyl)- N- hydroxy- propanimidamide hydrochloride 52 30.3 m/z 491 [MH]⁺ RT 3.67 min 3-butyl-8-chloro-1-(3-{3-[1-(4- chlorophenyl)ethyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione NMR Details for Selected Examples from Table 5

Example 115

¹H NMR (d⁶ DMSO) 0.88 (3H, t, J=7 Hz), 1.24-1.33 (2H, m), 1.56-1.65 (2H, m), 1.98-2.06 (2H, m), 2.92 (2H, t, J=7 Hz), 3.89 (2H, t, J=7 Hz), 3.97 (2H, t, J=7 Hz), 4.14 (2H, s), 7.52-7.70 (4H, m).

Example 117 3-butyl-8-chloro-1-{3-[3-(1-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₈) δ: 0.89 (t, 31-1, J=7 Hz), 1.22-1.35 (m, 2H), 1.52 (d, 31-1, J=8 Hz), 1.56-1.68 (m, 2H), 1.95-2.08 (m, 2H), 2.91 (t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), 4.18 (q, 1H, J=8 Hz), 7.17-7.32 (m, 5H).

Example 119 3-butyl-8-chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7 Hz), 1.23-1.37 (m, 2H), 1.55-1.67 (m, 2H), 1.97-2.09 (m, 2H), 2.90 (t, 2H, J=7 Hz), 3.88 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7 Hz), 4.00 (s, 2H), 7.27-7.40 (m, 4H).

Example 122 3-butyl-8-chloro-1-(3-{3-[(4-hydroxyphenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.23-1.37 (m, 2H), 1.57-1.68 (m, 2H), 1.96-2.08 (m, 2H), 2.90 (t, 2H, J=7 Hz), 3.82 (s, 2H), 3.90 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 6.68 (d, 2H, J=9 Hz), 7.04 (d, 2H, J=9 Hz), 9.32 (s, 1H).

Example 123 3-butyl-8-chloro-1-[3-(3-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.23-1.36 (m, 2H), 1.57-1.69 (m, 2H), 1.95-2.08 (m, 2H), 2.95 (t, 2H, J=7 Hz), 3.91 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7 Hz), 5.62 (s, 2H), 6.79 (s, 1H), 8.10 (s, 1H).

Example 125 3-butyl-8-chloro-1-(3-{3-[1-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.23-1.38 (m, 2H), 1.51 (d, 3H, J=6 Hz), 1.55-1.69 (m, 2H), 1.96-2.10 (m, 2H), 2.92 (t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.24 (q, 1H, J=6 Hz), 7.27-7.40 (m, 4H).

Example 126 3-Butyl-8-chloro-1-[3-(3-{[3-(ethyloxy)-4-hydroxyphenyl]methyl}-1,2,4-oxadiazol-5-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-[3-(ethyloxy)-4-hydroxyphenyl]-N-hydroxyethanimidamide (35 mg, 0.165 mmol; entry 11, Table 7) were mixed in EtOH (0.75 ml). Ethanolic sodium ethoxide (21% by wt., 0.083 ml, 0.22 mmol) was added and the mixture was heated in the microwave at 140° C. for 10 min. A further 0.055 ml (0.15 mmol) of NaOEt solution was then added and the mixture heated for a further 10 min period at 140° C. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated and purified by MDAP to give the title compound as a solid (29.6 mg).

LC/MS: m/z 503 [MH]⁺, RT 3.15 min.

The following compounds (Table 6) were prepared using a method analogous to that for Example 126, using the appropriate amidoxime (with the exception that for Example 127 (Table 6), the crude product after workup was stirred with EtOH (1 ml) and 2M NaOH (0.5 ml) overnight in order to hydrolyse residual starting ester, prior to repeat HCl workup and purification by MDAP).

TABLE 6 Wt of Amidoxime aldoxime Yield Example Structure (see table 7) mg mg LC/MS: 127

12 32 19.3 m/z 489 [MH]⁺ RT 2.98 min 3-butyl-8-chloro-1-[3-(3-{(4- hydroxy-3- (methyloxy)phenyl]methyl}-1,2,4- oxadiazol-5-yl)propyl]-3,7-dihydro- 1H-purine-2,6-dione 128

13 32 37.2 m/z 487 [MH]⁺ RT 3.23 min 3-butyl-8-chloro-1-(3-{3-[1-(4- hydroxyphenyl)-1-methytethyl]- 1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 129

14 34 23.6 m/z 500 [MH]⁺ RT 2.94 min N-[3-({5-[3-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]-1,2,4-oxadiazol-3- yl}methyl)phenyl]acetamide NMR Details for Selected Examples from Table 6

Example 129 N-[3-({5-[3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]-1,2,4-oxadiazol-3-yl}methyl)phenyl]acetamide

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.25-1.38 (m, 2H), 1.57-1.68 (m, 2H), 1.95-2.07 (m, 5H), 2.92 (t, 2H, J=7 Hz), 3.91 (t, 2H, J=7 Hz), 3.94 (s, 2H), 3.98 (m, 2H), 6.88-7.50 (m, 4H), 9.90 (s, 1H).

Example 130 3-Butyl-8-chloro-1-(3-{3-[(2-chloro-4-fluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (100 mg, 0.28 mmol) and (1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (62.4 mg, 0.308 mmol) and 21% by wt. ethanolic sodium ethoxide (0.157 ml, 0.42 mmol) were heated together in a microwave reactor in EtOH (1.5 ml) at 140° C. for 10 min. The mixture was worked up by partitioning between EtOAc and 2M HCl. The organic phase was evaporated and purified by MDAP to afford the title compound as a solid (73 mg).

LC/MS: m/z 495 [MH]⁺, RT 3.55 min.

Example 131 8-Chloro-3-ethyl-1-{(3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-ethyl-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.59 mmol) in anhydrous THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (154 mg, 0.71 mmol) and triphenylphosphine (200 mg, 0.76 mmol). DBAD (162 mg, 0.71 mmol) was added in one portion and the mixture was left to stir at rt, under nitrogen for 18 h. The mixture was degassed by high vacuum then Pd(PPh₃)₄ (68 mg, 0.059 mmol) and morpholine (515 μl, 5.9 mmol) were added. The mixture was left to stir at rt, under nitrogen, for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated by high vacuum. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2% AcOH/MeOH to elute the compound. The UV active fractions were combined and concentrated by high vacuum. The product was further purified by MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (61 mg, 25%).

LC/MS: m/z 415 [MH]⁺, RT 3.01 min

¹H NMR; (DMSO-d₆) δ: 1.19 (t, 3H, J=7 Hz), 2.93 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 3.96 (m, 6H), 7.27 (m, 5H) 14.46 (s, 1H).

b) 8-Chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 0.044 mol) in anhydrous DMF (100 ml) was treated with iodoethane (5.4 ml, 0.068 mol) and Na₂CO₃ (4.9 g, 0.046 mol). The reaction mixture was left to stir at it under nitrogen for 2 days. Iodoethane (0.35 ml, 0.0044 mol) was added and the mixture was left to stir at it for 1 day. The mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed sequentially with saturated sodium sulphite solution and brine, dried (MgSO₄) and concentrated. The crude solid was washed with Et₂O to give the title compound as a white solid (8.37 g, 75%).

LC/MS: m/z 255 [MH]⁺, RT 2.35 min.

Example 132 8-Chloro-3-pentyl-1-(3-{3-[(1S,2S)-2-phenylcyclopropyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH (1.5 ml). The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1S,2S)—N-hydroxy-2-phenylcyclopropanecarboximidamide (37 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was separated and concentrated, the resulting crude product was purified by MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (35 mg, 38%).

LC/MS: m/z 483 [MH]⁺, RT 3.67 min.

Example 133 8-Chloro-1-(3-{3-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}Propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(3-chlorophenyl)-N-hydroxyethanimidamide (38 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (46 mg, 49%).

LC/MS: m/z 491 [MH]⁺, RT 3.64 min.

¹H NMR (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz), 1.27 (m, 4H), 1.62 (m, 2H), 2.02 (m, 2H), 2.92 (t, 2H, J=7.5 Hz), 3.88 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=6.5 Hz), 4.02 (s, 2H), 7.23 (d, 1H, J=7 Hz), 7.34 (m, 3H).

Example 134 8-Chloro-1-(3-{3-[(3,4-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (46 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (66 mg, 66%).

LC/MS: m/z 527 [MH]⁺, RT 3.80 min.

Example 135 8-Chloro-1-(3-{3-[(2,6-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(2,6-dichlorophenyl)-N-hydroxyethanimidamide (46 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated by nitrogen blowdown. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (80 mg, 80%).

LC/MS: m/z 526 [MH]⁺, RT 3.6 min.

Example 136 8-Chloro-1-(3-{3-[(2-chloro-4-fluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (42 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (65 mg, 67%).

LC/MS: m/z 509 [MH]⁺, RT 3.63 min.

Example 137 3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (205 mg, 0.73 mmol) in anhydrous THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (190 mg, 0.87 mmol) and PPh₃ (247 mg, 0.94 mmol). DBAD (217 mg, 0.94 mmol) was added in one portion and the mixture was stirred at it under nitrogen for 18 h. The mixture was degassed by high vacuum then Pd(PPh₃)₄ (84 mg, 0.073 mmol) and morpholine (636 μl, 7.3 mmol) were added. The mixture was stirred at it under nitrogen for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq) and the organic layer separated, washed with brine, dried (MgSO₄) and concentrated. The crude material was purified by an aminopropyl column using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH gradient to remove the compound from the column. Further purification was effected by MDAP to give the title compound as a white solid (75 mg, 23%).

LC/MS: m/z 443 [MH]⁺, RT 3.37 min.

¹H NMR; (DMSO-d₆) δ: 0.89 (t, 3H, J=7.5 Hz), 1.29 (m, 2H), 1.61 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 3.89 (t, 2H, J=7 Hz), 3.97 (m, 4H), 7.27 (m, 5H) 14.46 (s, 1H).

Example 138 8-Chloro-1-(3-{3-[(4-hydroxyphenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (29 mg, 0.078 mmol) and (1Z)-N-hydroxy-2-(4-hydroxyphenyl)ethanimidamide (14 mg, 0.084 mmol) were heated in EtOH (1 ml) with 21% ethanolic sodium ethoxide (0.043 ml, 0.117 mmol) under microwave irradiation at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated. This material was stirred with EtOH (1 ml) and 2M NaOH (0.5 ml) for 18 h, before being worked up again by partition between EtOAc and 2M HCl. Purification by MDAP afforded the title compound (6.5 mg).

LC/MS: m/z 473 [MH]⁺, RT 3.34 min.

¹H NMR (MeOH-d₄) δ: 0.92 (t, 3H, J=7 Hz), 1.25-1.45 (m, 4H), 1.68-1.78 (m, 2H), 2.11-2.21 (m, 2H), 2.93 (t, 2H, J=7 Hz), 3.82 (s, 2H), 3.98 (t, 2H, J=7 Hz), 4.10 (t, 2H, J=7 Hz), 6.70 (d, 2H, J=10 Hz), 7.02 (d, 2H, J=10 Hz).

Example 139 3-Butyl-8-chloro-1-(3-{3-[(phenyloxy)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

To ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (26 mg, 0.073 mmol) and (1Z)-N-hydroxy-2-(phenyloxy)ethanimidamide hydrochloride (16 mg, 0.079 mmol) in EtOH (1 ml) was added 21% wt. ethanolic sodium ethoxide solution (0.068 ml, 0.183 mmol) and the mixture was heated under microwave irradiation at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl, the organic phase dried (Na₂SO₄) evaporated and purified by MDAP to give title compound as a gum which solidified upon trituration with ether (5.9 mg).

LC/MS: m/z 459 [MH]⁺, RT 3.39 min.

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=8 Hz), 1.22-1.36 (m, 2H), 1.57-1.68 (m, 2H), 2.02-2.14 (m, 2H), 3.00 (t, 2H, J=8 Hz), 3.90 (t, 2H, J=7 Hz), 4.00 (t, 2H, J=7 Hz), 5.18 (s, 2H), 6.95-7.35 (m, 5H).

Example 140 3-Butyl-8-chloro-1-(3-{3-[(3,5-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

To ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (185 mg, 0.52 mmol) and (1Z)-2-(3,5-dichlorophenyl)-N-hydroxyethanimidamide (126 mg, 0.58 mmol; Entry 23, Table 7) in dry EtOH (2 ml) was added 21% wt. ethanolic sodium ethoxide solution (0.29 ml, 0.78 mmol) and the mixture was heated by microwaves at 140° C. for 10 min. The reaction was worked up by partition between EtOAc and 2M HCl and evaporating the organic phase. Purification by MDAP afforded the title compound as a solid (135 mg).

LC/MS: m/z 511 [MH]⁺, RT 3.71 min.

Example 141 3-Butyl-8-chloro-1-(3-{3-[(2,4,6-trifluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

Similarly prepared starting from (1Z)-N-hydroxy-2-(2,4,6-trifluorophenyl)ethanimidamide (119 mg, 0.58 mmol; Entry 24, Table 7) in a yield of 135 mg.

LC/MS: m/z 497 [MH]⁺, RT 3.39 min.

¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, J=7 Hz), 1.24-1.36 (m, 2H), 1.55-1.66 (m, 2H), 1.96-2.06 (m, 2H), 2.91 (t, 2H, J=8 Hz), 3.91 (t, 2H, J=8 Hz), 3.94-4.02 (m, 4H), 7.18-7.28 (m, 2H).

Amidoximes:

These are available by the methods detailed below and exemplified by analogues in Table 7.

TABLE 7 (Intermediates) Yield Entry Structure Name Method mg LC/MS: 1

(1Z)-2-(2-chlorophenyl)-N- hydroxyethanimidamide G 38 m/z 185 [MH]⁺ RT 1.04 min 2

(1Z)-2-(4-fluorophenyl)-N- hydroxyethanimidamido G 42 m/z 169 [MH]⁺ RT 0.72 min 3

(1Z)-2-(2,3-dichlorophenyl)-N- hydroxyethanimidamide B 64 m/z 219 [MH]⁺ RT 1.83 min 4

(1Z)-2-(3-fluorophenyl)-N- hydroxyethanimidamide A 78 m/z 169 [MH]⁺ RT 0.62 min 5

(1Z)-2-(3,4-difluorophenyl)-N- hydroxyethanimidamide A 88 m/z 187 [MH]⁺ RT 0.74 min 6

(1Z)-2-(3-chloro-2- fluorophenyl)-N- hydroxyethanimidamide A 92 m/z 203 [MH]⁺ RT 1.40 min 7

(1Z)-N-hydroxy-2-(3- hydroxyphenyl)ethanimidamide A 67 m/z 167 [MH]⁺ RT 0.46 min 8

N-hydroxy-1- phenylcyclopropanecarboximi- damide C 75 m/z 177 [MH]⁺ RT 1.06 min 9

(1Z)-2-(3-bromophenyl)-N- hydroxy-2- methylpropanimidamide D 74 m/z 257 [MH]⁺ RT 2.04 min 10

(1Z)-2-(1,3-benzodioxol-5-yl)- N-hydroxyethanimidamide C 98 m/z 195 [MH]⁺ RT 0.73 min 11

(1Z)-2-[3-(ethyloxy)-4- hydroxyphenyl]-N- hydroxyethanimidamide C 109 m/z 211 [MH]⁺ RT 0.76 min 12

(1Z)-N-hydroxy-2-[4-hydroxy-3- (methyloxy)phenyl]ethanimidamide C 98 m/z 197 [MH]⁺ RT 0.50 min 13

(1Z)-N-hydroxy-2-(4- hydroxyphenyl)-2- methylpropanimidamide D 66 m/z 195 [MH]⁺ RT 0.85 min 14

N-{3-((2Z)-2-(hydroxyamino)-2- iminoethyl]phenyl}acetamide C 91 m/z 208 [MH]⁺ RT 0.73 min 15

(1Z)-N-hydroxy-2-(2,3,4- trichlorophenyl)ethanimidamide C 124 m/z 253 [MH]⁺ RT 2.29 min 16

(1Z)-2-(2,5-difluorophenyl)-N- hydroxyethanimidamide C 89 m/z 187 [MH]⁺ RT 0.66 min 17

(1Z)-2-(2,6-difluorophenyl)-N- hydroxyethanimidamide C 86 m/z 187 [MH]⁺ RT 0.62 min 18

(1Z)-2-(3,5-difluorophenyl)-N- hydroxyethanimidamido C 96 m/z 187 [MH]⁺ RT 0.80 min 19

(1Z)-2-(2-chloro-5- fluorophenyl)-N- hydroxyethanimidamide C 97 m/z 203 [MH]⁺ RT 0.90 min 20

(1Z)-N-hydroxy-2-(1H-indol-3- yl)ethanimidamide C 95 m/z 190 [MH]⁺ RT 0.90 min 21

(1Z)-N-hydroxy-2-(2- thienyl)ethanimidamide C 74 m/z 157 [MH]⁺ RT 0.38 min 22

(1Z)-2-(1-benzofuran-3-yl)-N- hydroxyethanimidamide C 87 m/z 191 [MH]⁺ RT 1.46 min 23

(1Z)-2-(3,5-dichlorophonyl)-N- hydroxyethanimidamide E 165 m/z 219 [MH]⁺ RT 2.03 min 24

(1Z)-N-hydroxy-2-(2,4,6- trifluorophenyl)ethanimidamide F 297 m/z 205 [MH]⁺ RT 0.66 min 25

(1Z)-N-hydroxy-2-{3- [(methylsulfonyl)amino]phenyl} ethanimidamide C 125 m/z 244 [MH]⁺ RT 0.63 min

Method A

The corresponding nitrile (0.5 mmol) was stirred in EtOH (1.5 ml) with 50% aqueous hydroxylamine solution (0.08 ml, 1.3 mmol) and heated at 65° C. for 4.5 h. After cooling the crude reaction mixture was loaded onto an SCX SPE cartridge (2 g) and washed with MeOH, then the amidoxime product was eluted with 2M ammonia in MeOH.

Method B

Similar to Method A except that the product crystallised out from the crude reaction mixture and was isolated by filtration instead of by SCX.

Method C

Similar to Method A except that the product was purified on a 5 g SCX cartridge.

Method D

Similar to Method C except that the heating period was 18 h.

Method E

Similar to Method C except that the scale was 0.753 mmol of nitrile.

Method F

Similar to Method A except that the scale was 1.5 mmol of nitrile and purification was on a 10 g SCX cartridge.

Method G

Similar to Method A except that the heating time was 2.75 h and the scale was 0.25 mmol of nitrile.

It should be noted that the above assignment of (Z)-stereochemistry has not been confirmed by experimental data. The person skilled in the art will also recognise that there can be interconversion between E & Z isomers. (Dondoni, Alessandro; Lunazzi, Lodovico; Giorgianni, Patrizia; Macciantelli, Dante. Carbon-nitrogen rotational barrier as a stereochemical probe of benzamidoximes. Journal of Organic Chemistry (1975), 40(20), 2979-80)

Example 142 3-Butyl-8-chloro-1-(3-{5-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-(3-{5-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}Propyl)-3,7-dihydro-1H-purine-2,6-dione

(3-Chlorophenyl)acetic acid (0.1 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol) and 1H-1,2,3-benzotriazol-1-ol (15 mg, 0.11 mmol) were stirred in 1-methyl-2-pyrrolidinone (1 ml). To this was added (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (34 mg, 0.1 mmol) and the mixture stirred at rt for 17 h and then at 80° C. for 24 h. The reaction mixture was purified, without further modification, by preparative HPLC (auto prep) to give the title compound (13 mg, 27%).

LC/MS: m/z 477, 479 [MH]⁺, RT 3.5 min.

¹H NMR (CDCl₃) δ: 0.96 (t, 3H, J=7 Hz), 1.32-1.47 (m, 2H), 1.68-1.80 (m, 2H), 2.12-2.24 (m, 2H), 2.83 (t, 2H, J=7.5 Hz), 4.05-4.24 (m, 6H), 7.16-7.30 (m, 4H).

b) (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide

4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanenitrile (1 g, 0.0032 mol) was stirred in EtOH (3.5 ml) and water (1.8 ml). Hydroxylamine hydrochloride (344 mg, 0.0049mol) and potassium carbonate (652 mg, 0.0049mol) were added and the mixture heated at 80° C. for 3 days. After cooling the crude reaction mixture was evaporated. The crude product was dissolved in water, neutralised to pH7 with HCl, and loaded onto an Oasis™ cartridge (2 g). This was eluted with water to remove the salts and then with MeOH, to give the title compound (957 mg, 86%).

LC/MS: m/z 343, 345 [M]⁺, RT 2.04 min.

c) 4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanenitrile

4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanenitrile (2.1 g, 6 mmol) was stirred in a mixture of nitrogen degassed DCM (20 ml) and AcOH (2 ml). Tetrakis(triphenylphosphine)palladium (675 mg, 0.6 mmol) and phenyl silane (7.4 ml, 60 mmol) were added and the mixture stirred at rt for 2d. This was then evaporated and the residue triturated with a mixture of diethylether:cyclohexane (1:1) to afford the title compound (1.47 g, 60%) as a white solid.

LC/MS: m/z 310 [MH]⁺, RT 2.66 min.

d) 4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanenitrile

3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 0.0072 mol) in dry MeCN (20 ml) was added Cs₂CO₃ (4.68 g, 0.0144 mol) followed by bromobutyronitrile (1.38 g, 0.0094 mol). The mixture was heated at 80° C. for 18 h and then allowed to cool. The reaction mixture was evaporated and the crude product partitioned between EtOAc and HCl (2N). The organic phase was separated and washed with brine, dried (MgSO₄) and evaporated to give the crude product. This was purified by silica SPE (50 g), eluting with cyclohexane:ethylacetate (2:1 to 1:1) to afford the title compound as a clear oil (2.1 g, 85%).

LC/MS: m/z 350 [MH]⁺, RT 3.10 min.

The following compounds (Table 8) were prepared using a method analogous to that for Example 142, from the corresponding acids and (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide.

TABLE 8

Example Compound: R1 = Yield % LC/MS: 143 3-butyl-8-chloro-1-(3-{5-[(3- chlorophenyl)methyl]-1,2,4- oxadiazol-3-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione

27 m/z 477 [MH]⁺ RT 3.5 min 144 3-butyl-8-chloro-1-[3-(5-{[3- (methyloxy)phenyl]methyl}- 1,2,4-oxadiazol-3-yl)propyl]- 3,7-dihydro-1H-purine-2,6- dione

22 m/z 473 [MH]⁺ RT 3.3 min 145 3-butyl-8-chloro-1-[3-(5-{[3- (trifluoromethyl)phenyl]methyl}- 1,2,4-oxadiazol-3- yl)propyl]-3,7-dihydro-1H- purine-2,6-dione

23 m/z 511 [MH]⁺ RT 3.5 min 146 3-butyl-8-chloro-1-(3-{5-[(2- chloro-4- fluorophenyl)methyl]-1,2,4- oxadiazol-3-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione

28 m/z 495 [MH]⁺ RT 3.5 min 147 3-butyl-8-chloro-1-{3-[5- (cyclopentylmethyl)-1,2,4- oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione

15 m/z 435 [MH]⁺ RT 3.5 min 148 1-{3-[5-(1,3-benzodioxol-5- ylmethyl)-1,2,4-oxadiazol-3- yl]propyl}-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6- dione

27 m/z 487 [MH]⁺ RT 3.3 min 149 3-butyl-8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]-1,2,4- oxadiazol-3-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione

28 m/z 461 [MH]⁺ RT 3.3 min 150 3-butyl-8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]methyl}- 1,2,4-oxadiazol-3-yl)propyl]- 3,7-dihydro-1H-purine-2,6- dione

21 m/z 473 [MH]⁺ RT 3.3 min 151 1-{3-[5-(1-benzofuran-4- ylmethyl)-1,2,4-oxadiazol-3- yl]propyl}-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6- dione

24 m/z 483 [MH]⁺ RT 3.4 min NMR Details for Selected Examples from Table 8

Example 145

¹H NMR (CDCl₃) 0.96 (3H, t, J=7.5 Hz), 1.32-1.47 (2H, m), 1.65-1.81 (2H, m), 2.12-2.25 (2H, m), 2.84 (2H, t, J=7.5 Hz), 4.02 (2H, t, 7.5 Hz), 4.22 (2H, t, 7 Hz), 4.24 (2H, s), 7.40-7.62 (4H, m).

Example 152 8-Chloro-3-pentyl-1-{3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-1-{3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

To a stirred solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20, 0.67 mmol) in THF (5 ml) was added 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (0.162 g, 0.74 mmol), DBAD (0.186 g, 0.81 mmol) and triphenylphosphine (0.212 g, 0.81 mmol) and the solution stirred for 18 h. To the solution was added Pd(PPh₃)₄ (75 mg, 0.067 mmol) and morpholine (600 μl, 6.7 mmol) were added and stirred for at rt under nitrogen for a further 3 h. 75 mg of Pd(PPh₃)₄ was added and the mixture left to stir for another 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH to elute the compound. The product fractions were combined and concentrated then further purified by MDAP. The product fractions were combined and concentrated give the title compound as a white solid (51 mg, 20%).

LC/MS: m/z 457 [MH]⁺, RT 3.54 min.

b) 3-[5-(Phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol

A mixture of (1E)-4,4-bis(ethyloxy)-N-hydroxybutanimidamide (3.2 g, 16.8 mmol), ethyl phenylacetate (2.3 ml, 14.4 mmol) and sodium ethoxide (21% solution in EtOH, 6.4 ml) was heated in a microwave at 140° C. for 10 min. The material was combined with that from a second reaction (using 1.2 g of (1E)-4,4-bis(ethyloxy)-N-hydroxybutanimidamide and conducted as above) and partitioned between 1M HCl solution and EtOAc. The organic layer was separated, washed with brine, dried and concentrated to provide 5-[3,3-bis(ethyloxy)propyl]-5-(phenylmethyl)-1,2,4-oxadiazole which was used without purification in the next stage.

Crude 3-[3,3-bis(ethyloxy)propyl]-5-(phenylmethyl)-1,2,4-oxadiazole (5.63 g, 19.4 mmol) in EtOH (75 ml) was stirred with p-toluenesulphonic acid (0.738 g, 3.9 mmol) for 21 h and the mixture partitioned between EtOAc and water. The organics were isolated washed with water and brine, dried and concentrated to a red oil. This material contained significant amounts of acetal, therefore the oil was dissolved in THF (15 ml) and treated with 2M HCl solution for 2 h then partitioned between EtOAc and water. The organics were isolated washed with brine, dried and concentrated to yield 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propanal as a red/brown oil (3.77 g) which was used crude in the next stage.

A solution of crude 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propanal (3.76 g, 17.4 mmol) in MeOH (60 ml) was cooled to 0° C. and sodium borohydride (0.724 g, 19.1 mmol) added portionwise over 30 min. The cooling bath was removed and the solution stirred for a further 1 h then partitioned between 1M HCl and EtOAc. The organic layer was separated and the aqueous extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to an orange liquid. This was purified on a 50 g silica SPE eluting with cyclohexane/EtOAc (20% to 80% gradient elution) to provide the title compound as a yellow oil (2.24 g).

LC/MS: m/z 210 [MH]⁺.

c) (1E)-4,4-bis(ethyloxy)-N-hydroxybutanimidamide

A mixture of 3-cynopropionaldehyde diethylacetal (6.12 g, 39 mmol), hydroxylamine hydrochloride (4.06 g, 58.4 mmol), potassium carbonate (10.76 g, 77.9 mmol) in water (20 ml) and EtOH (40 ml) was refluxed for 24 h. The mixture was allowed to cool and then partitioned between water and EtOAc. The organic layer was separated and the aqueous extracted with EtOAc. The combined organic fractions were washed with brine, dried and concentrated to provide the title compound as a colourless oil contaminated with ˜20% starting nitrile (6.03 g, 81%).

LC/MS: m/z 191 [MH]⁺.

Example 153 8-Chloro-1-{3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3-propyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (195 mg, 0.89 mmol) and PPh₃ (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated by high vacuum. The crude product was purified on a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated by high vacuum and purified on a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh₃)₄ (61 mg, 0.053 mmol) and morpholine (460 μl, 5.3 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated to leave the title compound as a white solid (36 mg, 11%).

LC/MS: m/z 429 [MH]⁺, RT 3.14 min.

¹H NMR (DMSO-d₆) δ: 0.86 (t, 3H, J=7.5 Hz), 1.65 (m, 2H), 1.93 (m, 2H), 2.70 (t, 2H, J=7.5 Hz), 3.86 (t, 2H, J=7 Hz), 3.96 (t, 2H, J=7 Hz), 4.28 (s, 2H), 7.32 (m, 5H).

Example 154 3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (594 mg, 2.7 mmol) in THF (25 ml) was treated with 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (700 mg, 2.48 mmol) and PPh₃ (779 mg, 2.97 mmol) under nitrogen. DBAD (684 mg, 2.97 mmol) was added in one portion and the reaction left to react for 60 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. MeOH was added to the residue and then passed down an aminopropyl column with the product eluting with 2-4% AcOH/MeOH. Product fractions were combined and concentrated. The off-white residue was recrystallised from EtOAc:cyclohexane (1:1), giving the title compound as a white solid (696 mg, 63%).

LC/MS: m/z 443 [MH]⁺, RT 3.4 min.

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7 Hz), 1.29 (m, 2H), 1.61 (m, 2H), 1.93 (m, 2H), 2.70 (t, 2H, J=7.5 Hz), 3.90 (t, 2H, J=7 Hz), 3.96 (t, 2H, J=7 Hz), 4.28 (2H, s), 7.31 (m, 5H), 14.4 (br s, 1H).

Example 155 3-Butyl-8-chloro-1-(3-{5-[(3-chloro-4-hydroxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-chloro-4-hydroxyphenylacetic acid (24 mg, 0.13 mmol) in DMSO (1 ml) was treated with CDI (21 mg, 0.13 mmol) and left to react for 30 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (50 mg, 0.15 mmol) was added and the mixture heated in the microwave at 120° C. for 15 min. The solution was directly purified by MDAP to obtain the title compound as a white solid (12 mg, 17%).

LC/MS: m/z 493 [MH]⁺, RT 3.2 min.

Example 156 3-Butyl-8-chloro-1-[3-(5-{[3-chloro-2-(methyloxy)phenyl]methyl}-1,2,4-oxadiazol-3-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

A mixture of [3-chloro-2-(methyloxy)phenyl]acetic acid (32 mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDI (26 mg, 0.16 mmol) and left to react for 45 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture heated in the microwave at 140° C. for 15 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by the MDAP. The title compound was obtained as a white solid (25 mg, 28%).

LC/MS: m/z 507 [MH]⁺, RT 3.5 min.

Example 157 3-Butyl-8-chloro-1-(3-{5-[(3-fluoro-4-hydroxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

A mixture of (3-fluoro-4-hydroxyphenyl)acetic acid (27 mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDI (26 mg, 0.16 mmol) and left to react for 45 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture heated in the microwave at 140° C. for 15 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by MDAP. The title compound was obtained as a white solid (10 mg, 12%).

LC/MS: m/z 477 [MH]⁺, RT 3.2 min.

Example 158 8-chloro-3-pentyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione a) Preparation of 8-chloro-3-pentyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione

Benzoic acid (18 mg, 0.15 mmol) was treated with a solution of 1H-1,2,3-benzotriazol-1-ol hydrate (25 mg, 0.19 mmol) in DMSO (0.3 ml). To this was added a solution/suspension of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) in DMSO (0.3 ml) followed by a solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (55 mg, 0.15 mmol) in DMSO (0.3 ml). The mixture was heated at 40° C. for 1 h, then at 80° C. for 5 h and then cooled. The mixture was subjected to purification by MDAP. Product-containing fractions were blown to dryness by a stream of nitrogen to yield the title compound as a white solid (17.2 mg, 25%).

LC/MS: m/z 457 [MH]⁺, RT 3.67 min.

¹H NMR (CDCl₃) δ: 0.90 (t, 3H, J=6.8 Hz), 1.35 (m, 4H), 1.76 (m, 2H), 1.89 (m, 4H), 2.88 (t, 2H, J=7.2 Hz), 4.08 (t, 2H, J=7.5 Hz), 4.17 (t, 2H, J=6.7 Hz), 7.50 (m, 2H), 7.57 (m, 1H), 8.08, (d, 2H, J=7.3 Hz).

b) 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide

A solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile (3.0 g, 8.9 mmol) in EtOH (30 ml) was treated with water (15 ml), potassium carbonate (1.48 g, 10.7 mmol) and hydroxylamine hydrochloride (0.74 g, 10.7 mmol) and then heated at 70° C. overnight. A further potassium carbonate (1.5 g, 10.9 mmol) and hydroxylamine hydrochloride (1.0 g, 14.5 mmol) were cautiously added to the mixture which was then heated to 90° C. for 24 h. The mixture was cooled and concentrated in vacuo to remove most of the EtOH. The residual mixture was treated with water (30 ml) and acidified to pH 7 by the cautious addition of 2M aqueous hydrochloric acid. The precipitated solid was filtered off, washed with water, then with diethyl ether and thoroughly dried to yield the title compound as a white solid (2.80 g, 85%).

LC/MS: m/z 371 [MH]⁺, RT 2.27 min.

c) 5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile

A solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (4.0 g, 13.5 mmol) in DMF (100 ml) was treated with caesium carbonate (4.83 g, 14.8 mmol) and 5-bromopentanenitrile (1.73 ml, 14.8 mmol). The mixture was heated at 50° C. in a nitrogen atmosphere for 19 h and then cooled. The mixture was then degassed by the repeated successive application of a vacuum and then nitrogen pressure. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.94 mmol) and morpholine (11.8 ml, 136 mmol). The mixture was stirred in a nitrogen atmosphere for 3 h and then partitioned between EtOAc and 2M aqueous hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated to reveal a yellow, oily residue. This was dissolved in MeOH, divided equally into four portions and each portion applied to a 20 g aminopropyl SPE which was then washed through with MeOH. The desired product was eluted from the cartridge with a 5% v/v solution of AcOH in MeOH. The product-containing fractions were combined and concentrated to yield the title compound as a pale yellow solid (4.03 g, 88%).

LC/MS: m/z 338 [MH]⁺, RT 3.05 min.

The following compounds were prepared using a method analogous to that for Example 158 (8-chloro-3-pentyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione) from the corresponding acids:

TABLE 9 # Structure Name Yield LC/MS: 159

8-chloro-3-pentyl-1-{4-[5-(2- pyridinyl)-1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione 7.3 mg (11%) m/z 458 [MH]⁺ RT 3.21 min 160

8-chloro-1-{4-[5-(2- chlorophenyl)-1,2,4- oxodiazol-3-yl]butyl}-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 12.8 mg (17%) m/z 491 [MH]⁺ RT 3.77 min 161

8-chloro-1-(4-{5-[2- (methyloxy)phenyl]-1,2,4- oxodiazol-3-yl}butyl)-3- pentyl-3,7-dihydro-1H-purine- 2,6-dione 21.7 mg (30%) m/z 487 [MH]⁺ RT 3.54 min 162

8-chloro-1-(4-[5-(2- fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 16.6 mg (23%) m/z 475 [MH]⁺ RT 3.62 min

In addition Example 159, 8-chloro-3-pentyl-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione has the following spectral data: ¹H NMR (CDCl₃) δ: 0.89 (t, 3H, J=6.9 Hz), 1.75 (m, 4H), 1.89 (m, 6H), 2.92 (t, 2H, J=7.1 Hz), 4.07 (t, 2H, J=7.4 Hz), 4.16 (t, 2H, J=6.9 Hz), 7.52 (m, 1H), 7.92 (m, 1H), 8.18 (m, 1H), 8.83 (m, 1H), 13.40 (br s, 1H).

Example 163 8-Chloro-1-{4-[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]butyl}-3-propyl-3,7-dihydro-1H-purine-2,6-dione

4-Hydroxybenzoic acid (18 mg, 0.13 mmol) and CDI (24 mg, 0.15 mmol) were stirred in anhydrous DMSO (0.9 ml) at it for 1 h. (1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.15 mmol; prepared in a manner similar to (1Z)-5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide as described in Example 158(b)) was added and the mixture was stirred at 90° C. for 2 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated under high vacuum to give the title compound as a white solid (7 mg, 11%).

LC/MS: m/z 443 [MH]⁺, RT 3.28 min.

Example 164 3-Butyl-8-chloro-1-{4-[5-(2,6-difluorophenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

2,6-Difluorobenzoic acid (40 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at it for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (18 mg, 15%).

LC/MS: m/z 479 [MH]⁺, RT 3.40 min.

Example 165 3-Butyl-8-chloro-1-{4-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

2-Fluorobenzoic acid (36 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP. The product, fraction was combined and concentrated to give the title compound as a white solid (33 mg, 29%).

LC/MS: m/z 461 [M11]⁺, RT 3.44 min.

Example 166 3-Butyl-8-chloro-1-{4-[5-(4-chloro-2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

4-Chloro-2-pyridinecarboxylic acid (40 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (13 mg, 11%).

LC/MS: m/z 478 [MH]⁺, RT 3.31 min.

¹H NMR (DMSO-d₆) δ_(H) 14.4 (br. s, 1H), 8.79 (d, 1H, J=6 Hz), 8.24 (d, 1H, J=2 Hz), 7.88 (dd, 1H, J=6 Hz & 2 Hz), 3.91 (m, 4H), 2.85 (t, 2H, J=7.5 Hz), 1.56-1.76 (m, 6H), 1.28 (m, 2H), 0.87 (t, 3H, J=7.5 Hz) ppm.

Example 167 3-Butyl-8-chloro-1-{4-[5-(3-methyl-2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

3-Methyl-2-pyridinecarboxylic acid (35 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid 14 mg, 12%).

LC/MS: m/z 458 [MH]⁺, RT 3.13 min.

Example 168 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione Method A

2-Pyridinecarboxylic acid (31 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.5 ml) at rt for 1 h. A solution of (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) in DMSO (0.4 ml) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified directly by MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (14 mg, 12%).

LC/MS: m/z 444 [MH]⁺, RT 3.01 min.

¹H NMR (DMSO-d₆) δ: 0.87 (t, 3H, J=7 Hz), 1.27 (m, 2H), 1.65 (m, 6H), 2.84 (t, 2H, J=7 Hz), 3.91 (m, 4H), 7.70 (dd 1H, J=5 & 7 Hz), 8.07 (m, 1H), 8.19 (d, 1H, J=8 Hz), 8.81 (d, 1H, J=5 Hz), 14.5 (br. s, 1H).

Method B

2-Pyridinecarboxylic acid (675 mg, 5.3 mmol) and CDI (909 mg, 5.6 mmol) were stirred in anhydrous DMF (30 ml) at rt under nitrogen for 90 mins. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (2.0 g, 5.6 mmol) and DMF (10 ml) were added and the mixture was stirred at 100° C. for 20 h. The reaction mixture was cooled to rt then partitioned between sat. NH₄Cl(aq) solution and EtOAc. The organic layer was separated, and the aqueous solution extracted with EtOAc. The combined extracts were washed with brine, dried MgSO₄ and concentrated giving an orange liquid. This was purified using the Companion™ system giving two identical white solids (649 mg; 240 mg).

LC/MS: m/z 444 [MH]⁺, RT 3.04 min.

Method C

A 12-L, round-bottom flask was equipped with an overhead, mechanical stirrer, a temperature probe with a J-KEM temperature controller, a condenser and a nitrogen inlet adapter. The flask was charged with picolinic acid (0.180 kg, 1.46 mol), MIBK (4.0 L), 1,1′-carbonyldiimidazole (0.23 kg, 1.42 mol) and more MIBK (0.66 L). The mixture was stirred and warmed to 50° C. over approximately 1 hour, and the temperature overshot to 56° C. The solids dissolved during the heat up to 50° C. and carbon dioxide was generated. After 1 hour at 50° C., (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (0.467 kg, 1.31 mol) was added to the reaction. The mixture was then warmed to 90° C. over 1 hour. HPLC analysis of the reaction after heating at 90° C. for 5.5 hours indicated that the reaction was complete. The heat was turned off, and 1.0 N hydrochloric acid solution (2.33 L) was added. The temperature dropped to 61° C. After stirring overnight, the product precipitated and was filtered. The filtercake was washed with water (1×2.23 L, 1×2.43 L) and heptanes (1.40 L). The wet cake was dried in a vacuum oven at 50° C. for 22 hours to give 396 g of product (68%) HPLC analysis 97.7% (AUC) t_(R)=18.6 min.

Method D Formation of 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione Form 1

The reaction vessel was charged with 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1 wt), acetone (20vol) and water (0.6vol). The mixture was stirred and warmed to 50-60° C. and agitated for a minimum of 1 hour. A solution was formed which is clarified at this temperature by filtration through a 1 micron filter into a 2^(nd) reaction vessel. The solution was cooled over approximately 3 hours to 33-38° C. and seeded at this temperature with 3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-d lone (Form 1, 0.01 wt). The thin suspension was agitated at this temperature for a minimum of 1 hour then cooled to 20-25° C. and held at this temperature for a minimum of 12 hours. The suspension thus formed was cooled to 13-17° C. and held at this temperature for a minimum of 1 hour. The suspension was then sampled, and the solid collected by filtration in the laboratory. The solid was dried and analysed by xrpd/DSC to check form. If the form is as required (Form 1) the batch is filtered, washed (2×3vol acetone) and dried in a vacuum oven at 50° C. The batch is offloaded once analysis shows solvent levels (acetone, water) to be at acceptable.

Expected yield (75-80% w/w).

If the form of the sample taken at is shown to be other than pure Form 1, then the batch is reheated to 35-45° C. and agitated at this temperature for a minimum of 1 hour. The thin suspension is then cooled to 20-25° C. and held at this temperature for a minimum of 12 hours. The suspension thus formed is then cooled to 13-17° C. and held at this temperature for a minimum of 1 hour. The suspension is then sampled, and the solid collected by filtration in the laboratory. The solid is dried and analysed by xrpd/DSC to check form. If the form is as required (Form 1) the batch is filtered, washed and dried as described previously. If the form is not pure Form 1, then the cycle from is repeated until a satisfactory result is obtained.

X-Ray Powder Diffraction (XRPD)

X-ray powder diffraction (XRPD) data are shown in FIGS. 1-3. The data were acquired on a PANalytical X'Pert Pro powder diffractometer, model PW3040/60, serial number DY1850 using an X'Celerator detector. The acquisition conditions were: radiation: Cu Kα, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0°2θ, end angle: 40.0°2 θ, step size: 0.0167°2 θ, time per step: 31.75 seconds. The samples were prepared by mounting a few milligrams of sample on a Si wafer (zero background) plates, resulting in a thin layer of powder.

Example 169 3-Butyl-8-chloro-1-{4-[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

4-Hydroxybenzoic acid (35 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP to give the title compound as a white solid (5 mg, 4%).

LC/MS: m/z 459 [MH]⁺, RT 3.24 min.

Example 170 8-Chloro-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3-propyl-3,7-dihydro-1H-purine-2,6-dione

Benzoic acid (9 mg, 0.074 mmol) and CDI (13 mg, 0.081 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (28 mg, 0.081 mmol) was added and the mixture was stirred at 80° C. for 4 h. The mixture was purified by MDAP to give the title compound as a white solid (0.6 mg, 2%).

LC/MS: m/z 429 [MH]⁺, RT 3.21 min.

¹H NMR (MeOH-d₄) δ: 0.93 (t, 3H, J=7.5 Hz), 1.74 (m, 4H), 1.84 (m, 2H), 2.84 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7.5 Hz), 4.08 (t, 2H, J=7 Hz), 7.57 (dd, 2H, J=7 & 7.5 Hz), 7.65 (dd, 1H, J=7 & 7.5 Hz), 8.08 (d, 2H, J=7.5 Hz).

Example 171 3-Butyl-8-chloro-1-{4-[5-(2-chloro-6-fluorophenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

2-Chloro-6-fluorobenzoic acid (44 mg, 0.25 mmol) and CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (6.4 mg, 5%).

LC/MS: m/z 495 [MH]⁺, RT 3.58 min.

Example 172 3-Butyl-8-chloro-1-{4-[5-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

5-Hydroxy-2-pyridinecarboxylic acid (24 mg, 0.17 mmol) and CDI (31 mg, 0.19 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (68 mg, 0.19 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP and the product fractions concentrated to give the title compound as a white solid (19 mg, 24%).

LC/MS: m/z 459 [MH]⁺, RT 3.03 min.

Example 173 8-Chloro-3-pentyl-1-{4-[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1 ml) was treated with a 21% solution of NaOEt in EtOH (55 μl, 0.21 mmol) and ethyl 3-thiophenecarboxylate (18 μl, 0.13 mmol). The mixture was heated in the microwave at 150° C. for 10 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous extracted again with EtOAc. The combined extracts were concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (20 mg, 32%).

LC/MS: m/z 463 [MH]⁺, RT 3.6 min.

Example 174 8-Chloro-3-pentyl-1-{4-[5-(2-thienyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

2-Thiophenecarboxylic acid (14 mg, 0.11 mmol) was dissolved in NMP (0.9 ml) and treated with CDI (18 mg, 0.11 mmol). After 1 h, (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) was added and the mixture heated in the microwave at 150° C. for 15 min. The solution was directly purified by MDAP to obtain the title compound which was then freeze dried from 1,4-dioxane to give the title compound as a white solid (19 mg, 31%).

LC/MS: m/z 463 [MH]⁺, RT 3.5 min.

Example 175 8-Chloro-3-pentyl-1-{4-[5-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1.5 ml) was treated with a 21% solution of NaOEt in EtOH (50 μl, 0.13 mmol) and ethyl 1,3-thiazole-2-carboxylate (18 mg, 0.11 mmol). The mixture was heated in the microwave at 170° C. for 10 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by the MDAP. The title compound was obtained as a white solid (13 mg, 21%).

LC/MS: m/z 464 [MH]⁺, RT 3.3 min.

¹H NMR (DMSO-d₆) δ: 0.83 (t, 3H, J=7 Hz), 1.21-1.32 (m, 4H), 1.60-1.77 (m, 6H), 2.84 (t, 2H, J=7 Hz), 3.91 (m, 4H), 8.23 (d, 1H, J=3 Hz), 8.27 (d, 1H, J=3 Hz), 14.4 (br s, 1H).

Example 176 3-butyl-8-chloro-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione a) Preparation of 3-butyl-8-chloro-1-{-4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

To a mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (120 mg, 0.32 mmol) and of N-hydroxy-2-pyridinecarboximidamide (50 mg, 0.36 mmol) in EtOH (2 ml) was added a 21% (w/v) solution of sodium ethoxide in EtOH (0.225 ml, 0.62 mmol) and then heated in a sealed vial in a microwave oven at 140° C. for 10 min. The cooled mixture was evaporated to dryness and the residue partitioned between chloroform (5 ml) and saturated aqueous ammonium chloride (5 ml). The organic phase was evaporated to dryness and the crude product subjected to purification by MDAP. Product containing fractions were combined and evaporated to dryness. The product was triturated to a solid in a small amount of diethyl ether then dried to reveal the title compound as a white solid (44 mg, 31%).

LC/MS: m/z 444 [MH]⁺, RT 3.03 min.

¹H NMR (CDCl₃) δ: 0.96 (t, 3H, J=7.3 Hz), 1.40 (m, 2H), 1.74 (m, 2H), 1.88 (m, 2H), 1.99 (m, 2H), 3.07 (t, 2H, J=7.5 Hz), 4.09 (t, 2H, J=7.5 Hz), 4.17 (t, 2H, J=7.0 Hz), 7.43 (m, 1H), 7.64 (m, 1H), 8.10 (m, 1H), 8.79 (m, 1H).

b) Preparation of N-hydroxy-2-pyridinecarboximidamide

To a mixture of 2-pyridinecarbonitrile (3 g, 29 mmol) and potassium carbonate (4.1 g, 30 mmol)in EtOH (30 ml) was added water (15 ml) and, cautiously, hydroxylamine hydrochloride (2.9 g, 42 mmol) and then heated at reflux for 6 h, cooled and evaporated to dryness. The residue was treated with water (100 ml) and the suspended solid product filtered off, washed with water and dried to yield the title compound as a white solid (2.28 g, 57%).

¹H NMR (DMSO-d₆) δ: 5.85 (br s, 2H), 7.40 (m, 1H), 7.79 (m, 1H), 7.86 (m, 1H), 8.55 (m, 1H), 9.92 (s, 1H)

Example 177 3-Butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione Method A a) 3-Butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione

Ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (74 mg, 0.2 mmol) and benzamidoxime (30 mg, 0.22 mmol) were suspended in dry EtOH (1 ml) and ethanolic sodium ethoxide (21% by wt., 0.111 ml, 0.3 mmol) was added. The mixture was gently warmed until solids were dissolved and then heated in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase dried (Na₂SO₄) and evaporated. MDAP afforded the pure title compound (40.7 mg).

LC/MS: m/z 443 [MH]⁺, RT 3.67 min.

¹H NMR (DMSO-d₆) δ: 0.89 (t, 3H, J=7 Hz), 1.22-1.34 (m, 2H), 1.57-1.75 (m, 4H), 1.75-1.86 (m, 2H), 3.05 (t, 2H, J=7 Hz), 3.88-3.98 (m, 4H), 7.52-7.63 (m, 3H), 7.95-8.0 (m, 2H).

b) Ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate

To 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 5.31 mmol) in dry DMF (25 ml) was added Cs₂CO₃ (1.905 g, 5.84 mmol), followed by ethyl 5-bromovalerate (1.46 g, 6.99 mmol). The mixture was heated at 55° C. for 18 h then allowed to cool. It was degassed by repeatedly evacuating and readmitting nitrogen, then morpholine (3.70 ml, 42.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) were added and the mixture stirred for 5 h. EtOAc (75 ml), 2M HCl (40 ml) and water (20 ml) were added and the organic phase was separated, washed with brine (3×25 ml), filtered to remove some insoluble yellow solid, dried (Na₂SO₄) and evaporated. The residue (2.5 g) was purified by aminopropyl SPE (20 g), loading in THF-MeOH (1:1), washing with MeOH and eluting the product with DCM-MeOH (1:1) containing 5% added AcOH to afford the title compound (1.53 g).

LC/MS: m/z 371 MH⁺, RT 3.18 min

Method B a) 3-Butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione

CDI (0.98 g, 6.1 mmol) was added to a solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (1.89 g, 5.5 mmol) in DMF (15 ml) and stirred under nitrogen for 1.5 h. Benzamidoxime (0.91 g, 6.1 mmol) was added and the mixture stirred at 110° C. overnight. The reaction mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed with brine, dried (MgSO₄) and evaporated. The crude product was crystallised from methanol and then further purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a white solid (850 mg).

LC/MS: m/z 443 [MH]⁺, RT 3.52 min.

¹H NMR (MeOH-d₄) δ: 0.94 (t, 3H, J=7.5 Hz), 1.31-1.41 (m, 2H), 1.65-1.73 (m, 2H), 1.75-1.83 (m, 2H), 1.87-1.96 (m, 2H), 3.04 (t, 2H, J=7.5 Hz), 4.01 (t, 2H, J=7.5 Hz), 4.06 (t, 2H, J=7 Hz), 7.46-7.55 (m, 3H), 7.98-8.02 (m, 2H).

b) 5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid

A mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (2.8 g, 7.55 mmol), LiOH (542 mg, 22.7 mmol), water (2.5 ml) and methanol (50 ml) was stirred at rt for 60 h. The mixture was portioned between water and EtOAc and the pH of the aqueous phase adjusted to pH 4-5. The organic layer was separated, washed with brine, dried (MgSO₄) and evaporated to give the title compound as a white solid (2.18 g).

LC/MS: m/z 343 [MH]⁺, RT 2.69 min.

Example 178 8-Chloro-3-pentyl-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione

A mixture of methyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (50 mg, 0.13 mmol), benzamidine oxime (20 mg, 0.15 mmol) and a 21% solution of NaOEt in EtOH 0.20 mmol) in EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, dried (MgSO₄) and concentrated. Purification by the MDAP gave the title compound as a white solid (25 mg, 41%).

LC/MS: m/z 457 [MH]⁺, RT 3.7 min.

¹H NMR (DMSO-d₆) δ: 0.82 (t, 3H, J=7 Hz), 1.25 (m, 4H), 1.66 (m, 4H), 1.79 (m, 2H), 3.04 (t, 2H, J=7 Hz), 3.92 (4H, m), 7.57 (m, 3H), 7.97 (m, 2H), 14.5 (br s, 1H).

Example 179 3-Butyl-8-chloro-1-{4-[3-(3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (50 mg, 0.13 mmol), N,3-dihydroxybenzenecarboximidamide (25 mg, 0.16 mmol), 21% solution of NaOEt in EtOH (55 μl, 0.15 mmol) and EtOH (1.5 ml) was heated in the microwave at 180° C. for 10 min. Another aliquot of 21% solution of NaOEt in EtOH (55 μl, 0.21 mmol) was added and the mixture heated in the microwave at 175° C. for 30 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (20 mg, 32%).

LC/MS: m/z 459 [MH]⁺, RT 3.3 min.

Example 180 8-Chloro-1-{(4-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) in DMF (2 ml) was treated with CDI (23 mg, 0.14 mmol) and stirred at rt for 30 min. N,4-dihydroxybenzenecarboximidamide (26 mg, 0.17 mmol) was added and the mixture heated in the microwave at 120° C. for 15 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (17 mg, 26%).

LC/MS: m/z 473 [MH]⁺, RT 3.5 min.

Example 181 3-Butyl-8-chloro-1-[4-(5-phenyl-2H-tetrazol-2-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione

A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs₂CO₃ (45 mg, 0.14 mmol) and DMF (3 ml) was treated with 5-phenyl-1H-tetrazole (20 mg, 0.14 mmol) and stirred for 60 h at 50° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (20 mg, 0.017 mmol) was added and the mixture degassed once more. Morpholine (150 μl, 1.7 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an NH₂-propyl column with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as an off-white solid (15 mg, 29%).

LC/MS: m/z 443 [MH]⁺, RT 3.4 min.

¹H NMR (DMSO-d₆) δ: 0.86 (t, 3H, J=7 Hz), 1.26 (m, 2H), 1.59 (m, 4H), 1.97 (m, 2H), 3.90 (m, 4H), 4.76 (t, 2H, J=7 Hz), 7.54 (m, 3H), 8.02 (m, 2H), 14.4 (br s, 1H).

Example 182 3-Butyl-8-chloro-1-[4-(5-oxo-4-phenyl-4,5-dihydro-1H-tetrazol-1-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione

A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs₂CO₃ (45 mg, 0.14 mmol) and DMF (3 ml) was treated with 1-phenyl-1,2-dihydro-5H-tetrazol-5-one (23 mg, 0.14 mmol) and stirred for 60 h at 50° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (20 mg, 0.017 mmol) was added and the mixture degassed once more. Morpholine (150 μl, 1.7 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl column with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as an off-white solid (27 mg, 51%). NB. ca. 10% O-alkylated material present.

LC/MS: m/z 459 [MH]⁺, RT 3.1 min.

¹H NMR (DMSO-d₆) δ: 0.88 (t, 3H, J=7 Hz), 1.28 (m, 2H), 1.62 (m, 4H), 1.79 (m, 2H), 3.91 (m, 4H), 4.03 (m, 2H), 7.44 (m, 1H), 7.57 (m, 2H), 7.85 (m, 2H), 14.5 (br s, 1H).

Example 183 3-Butyl-8-chloro-1-[4-(4-methyl-2,5-dioxo-3-phenyl-1-imidazolidinyl)butyl]-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-[4-(4-methyl-2,5-dioxo-3-phenyl-1-imidazolidinyl)butyl]-3,7-dihydro-1H-purine-2,6-dione

A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (88 mg, 0.20 mmol), Cs₂CO₃ (80 mg, 0.24 mmol) and DMF (2 ml) was treated with 5-methyl-1-phenyl-2,4-imidazolidinedione (46 mg, 0.24 mmol) and stirred for 18 h at 70° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (25 mg, 0.022 mmol) was added and the mixture degassed once more. Morpholine (174 μL, 2.0 mmol) was added and the mixture was stirred under nitrogen for 5 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as a solid (70 mg, 71%).

LC/MS: m/z 487 [MH]⁺, RT 3.2 min.

b) 4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate

A solution of 3-butyl-8-chloro-1-(4-hydroxybutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.30 g, 3.66 mmol) in DCM (10 ml) was treated with triethylamine (0.77 ml, 5.50 mmol) followed by portionwise addition of methanesulfonic anhydride (702 mg, 4.03 mmol). CARE, effervescence. The reaction mixture was stirred at rt for 10 min then partitioned between sat. NaHCO₃ (aq) solution and DCM. The organic layer was separated and washed with 1M HCl (aq) and then brine. It was dried (MgSO₄) and concentrated, giving the title compound as a viscous oil (1.60 g, quant.).

LC/MS: m/z 433 [MH]⁺, RT 3.3 min.

c) 3-Butyl-8-chloro-1-(4-hydroxybutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

A stirred solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5.0 g, 17.7 mmol) in DMF (100 ml) was treated with Cs₂CO₃ (6.3 g, 19.5 mmol) and 4-bromo-1-butanol (3.0 ml, 21.2 mmol). The mixture was heated at 50° C. for 5 h then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow solid. Purification by silica SPE (EtOAc/cyclohexane mixtures as the eluent) and then by the Companion™ system (IPA/DCM mixtures as the eluent) gave the title compound as a colourless oil (1.35 g, 21%).

LC/MS: m/z 355 [MH]⁺, RT 2.9 min.

Example 184 8-Chloro-1-{4-[4-(cyclopentylsulfonyl)phenyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.34 mmol) was dissolved in DMF (1 ml) and sequentially treated with 4-[4-(cyclopentylsulfonyl)phenyl]-1-butanol (105 mg, 0.37 mmol), PPh₃ (404 μl of a 1M solution in DMF) and DBAD (404 μl of a 1M solution in DMF). After stirring for 24 h under nitrogen, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (39 mg, 0.034 mmol) was added and the mixture degassed once more. Morpholine (297 μl, 3.4 mmol) was added and the mixture was stirred under nitrogen for 63 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 2% AcOH/MeOH. The product was further purified by MDAP giving the title compound as a beige solid (5 mg, 3%).

LC/MS: m/z 521 [MH⁺], RT 3.7 min.

Example 185 8-Chloro-1-{4-[4-(methyloxy)phenyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 4-(4-bromobutyl)phenyl methyl ether (88 mg, 0.36 mmol) in DMF (3 ml) was reacted with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (90 mg, 0.30 mmol) and Cs₂CO₃ (109 mg, 0.33 mmol) for 5 h at 50° C. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (35 mg, 0.030 mmol) was added and the mixture degassed once more. Morpholine (0.26 ml, 3.0 mmol) was added and the mixture was stirred under nitrogen for 3 h. Another aliquot of Pd(PPh₃)₄ (35 mg, 0.030 mmol) was added and left for a further 3 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 3% AcOH/MeOH. The product was further purified by MDAP giving the title compound as a solid (2 mg, 1.5%).

LC/MS: m/z 419 [MH]⁺, RT 3.7 min.

¹H NMR; (MeOH-d₄) δ: 0.90 (t, 3H, J=7 Hz), 1.28-1.40 (m, 4H), 1.57-1.75 (m, 6H), 2.57 (t, 2H, J=7 Hz), 3.73 (s, 3H), 3.97-4.02 (4H, m), 6.77 (m, 2H), 7.06 (m, 2H).

Example 186 8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-3,7-dihydro-1H-purine-2,6-dione b)

8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.94 g) was dissolved in anhydrous THF (40 ml). The solution was degassed using a nitrogen/vacuum purge 6 times. Tetrakis(triphenylphosphine) palladium (0.66 g) was added followed by morpholine (5 ml). After stirring for 18 hr, the reaction mixture was diluted with EtOAc and was washed with 1N HCl and brine (×2), dried (MgSO₄) and evaporated in vacuo. This crude material was purified on an aminopropyl SPE (70 g) eluting with MeOH then MeOH containing 3% AcOH to give the title compound as a pale yellow solid (1.56 g).

LC/MS: m/z 405 [MH]⁺, RT 3.51 min.

b) 8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.76 g, 5.94 mmol) and 3-[3-(methyloxy)phenyl]-1-propanol (1.00 g, 6.04 mmol) were dissolved in anhydrous THF (50 ml) under an atmosphere of nitrogen. After 5 min triphenylphosphine (1.87 g, 7.12 mmol) was added. After a further 5 min di-tert-butyl azodicarboxylate (1.64 g, 7.1 mmol) was added. The solution was stirred for 20 h at rt. The cloudy solution was concentrated in vacuo and purified on a 50 g Silica II SPE (IST) using a Biotage FlashMaster™ Personal, eluting with cyclohexane /EtOAc 5:1 the appropriate fractions were concentrated in vacuo to give the title compound as a pale cream oil containing minor impurities (2.94 g).

LC/MS: m/z 445 [MH]⁺, RT 3.88 min.

Example 187 8-Chloro-1-[3-(3-hydroxyphenyl)propyl]-3-pentyl-3,7-dihydro-1H purine-2,6-dione

To a suspension of 8-chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-3,7-dihydro-1H-purine-2,6-dione (1.52 g, 3.86 mmol) in anhydrous DCM (40 ml) at −73° C. was slowly added 1N borontribromide in DCM (4.6 ml). The reaction mixture was stirred at −70° C. for 2 hours and then at rt for 96 h. The reaction mixture was cooled in ice, and water (6.8 ml) was added slowly. The reaction mixture was then diluted with EtOAc and water, and the organic phase was washed with saturated, sodium hydrogen carbonate (×3) and brine then dried (MgSO₄) and evaporated in vacuo. A portion of this crude material (90 mg) was purified by MDAP to give the title compound after freeze drying as a white solid (40 mg).

LC/MS: m/z 391 [MH]⁺, RT 3.43 min.

¹H NMR (DMSO-d₆) δ: 0.85 (t, 3H, J=7 Hz); 1.27 (m, 4H); 1.63 (m, 2H); 1.80 (m, 2H); 2.50 (m, 2H); 3.89 (m, 4H); 6.57 (m, 3H); 7.02 (t, 1H, J=8 Hz); 9.22 (s, 1H); 14.39 (s, 1H)

Example 188 3-butyl-8-chloro-1-{4-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A stirred solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (100 mg, 0.29 mmol) in DMF (4 ml) was treated with CDI (52 mg, 0.32 mmol). After 1 h, N,4-dihydroxybenzenecarboximidamide was added and the mixture heated at 100° C. for 6 h. On cooling, the reaction mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. Purification by MDAP afforded the title compound as a pale grey solid (72 mg).

LC/MS: m/z 459 [MH]⁺, RT 3.27 min.

The following compounds (Table 10) were prepared using a method analogous to that for Example 177, using the appropriate amidoxime.

TABLE 10 Yield Example Structure (mg) LC/MS 189

48.4 m/z 457 [MH]⁺ RT 3.56 min 3-butyl-8-chloro-1-{4-[3-(phenylmethyl)- 1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 190

35.8 m/z 461 [MH]⁺ RT 3.74 min 3-butyl-8-chloro-1-{4-[3-(4-fluorophenyl)- 1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 191

48.2 m/z 509 [MH]⁺ RT 3.74 min 3-butyl-8-chloro-1-(4-{3-[(2-chloro-4- fluorophenyl)methyl]-1,2,4-oxadiazol-5- yl}butyl)-3,7-dihydro-1H-purine-2,6-dione

Example 192 3-Butyl-8-chloro-1-{3-[3-(1-phenylcyclopentyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol), N-hydroxy-1-phenylcyclopentanecarboximidamide (34 mg, 0.165 mmol) and sodium methoxide (20 mg, 0.37 mmol) in dry MeOH (0.75 ml) were heated at 140° C. in the microwave reactor for 10 min. The mixture was then partitioned between ethyl acetate and 2M HCl, the organic phase evaporated and the product purified by MDAP to give the title compound as a solid (29.1 mg).

LC/MS: m/z 497 [MH]⁺, RT 3.76 min.

The following compounds (Table 11) were prepared using a method analogous to that for Example 192, using the appropriate amidoxime [with the exception that for Examples 210, 211 and 212 EtOH was used as reaction solvent; for Examples 210, 211 and 212 the reactions were worked up by adding 2M HCl until neutral and evaporating the solvent; for Example 206 the scale was 32 mg of starting ethyl ester; Example 208 the scale was 42 mg of starting ethyl ester].

TABLE 11 Yield Example Structure (mg) LC/MS 193

17.4 m/z 485 [MH]⁺ RT 3.74 min 3-butyl-8-chloro-1-{3-[3-(2-methyl- 1-phenylpropyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 194

33.7 m/z 515 [MH]⁺ RT 3.73 min 3-butyl-8-chloro-1-(3-{3-[1-(2- fluorophenyl)cyclopentyl}-1,2,4- oxadiazol-5-yl)propyl)-3,7-dihydro- 1H-purine-2,6-dione 195

28.8 m/z 455 [MH]⁺ RT 3.43 min 1-[3-(3-bicyclo[4.2.0]octa-1,3,5- trien-7-yl-1,2,4-oxadiazol-5- yl)propyl]-3-butyl-8-chloro-3,7- dihydro-1H-purine-2,6-dione 196

33.4 m/z 507 [MH]⁺ RT 3.59 min 3-butyl-8-chloro-1-(3-{3-[1-(2,4- difluorophenyl)-1-methylethyl]- 1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 197

33.8 m/z 517 [MH]⁺ RT 3.85 min 3-butyl-8-chloro-1-(3-{3-[1-(4- chlorophenyl)cyclobutyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 198

34.2 m/z 515 [MH]⁺ RT 3.80 min 3-butyl-8-chloro-1-(3-{3-[1-(3- fluorophenyl)cyclopentyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 199

16.3 m/z 505 [MH]⁺ RT 3.80 min 3-butyl-8-chloro-1-(3-{3-[1-(4- chlorophenyl)propyl]-1,2,4- oxadiazol-5-yl)propyl)-3,7-dihydro- 1H-purine-2,6-dione 200

34.9 m/z 549 [MH]⁺ RT 3.72 min 1-(3-{3-[1-(3- bromophenyl)cyclopropyl]-1,2,4- oxadiazol-5-yl}propyl)-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6- dione 201

30.4 m/z 507 [MH]⁺ RT 3.59 min 3-butyl-8-chloro-1-(3-{3-[1-(2,3- difluorophenyl)-1-methylethyl]- 1,2,4-oxadiazol-5-yl]propyl)-3,7- dihydro-1H-purine-2,6-dione 202

3 m/z 535 [MH]⁺ RT 3.69 min. 3-butyl-8-chloro-1-(3-{3- (phenoxy(phenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 203

38.8 m/z 577 [MH]⁺ RT 3.99 min. 1-(3-{3-[1-(3- bromophenyl)cyclopentyl]-1,2,4- oxadiazol-5-yl}propyl)-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6- dione 204

41.4 m/z 535 [MH]⁺ RT 3.79 min. 3-butyl-8-chloro-1-(3-{3-[1-(2- chloro-5-fluorophenyl)cyclobutyl]- 1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 205

12.9 m/z 499 [MH]⁺ RT 3.42 min. 3-butyl-8-chloro-1-{3-[3-(1,3,4,5- tetrahydro-2-benzoxepin-1-yl)- 1,2,4-oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione 206

12.9 m/z 563 [MH]⁺ RT 4.02 min. 3-butyl-8-chloro-1-(3-{3-[1-(2- chloro-6-fluorophenyl)cyclohexyl]- 1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 207

34.8 m/z 511 [MH]⁺ RT 3.88 min. 3-butyl-8-chloro-1-{3-[3-(1- phenylcyclohexyl)-1,2,4-oxadiazol- 5-yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 208

19 m/z 563 [MH]⁺ RT 4.00 min. 3-butyl-8-chloro-1-(3-{3-[1-(2- chloro-4-fluorophenyl)cyclohexyl]- 1,2,4-oxadiazol-5-yl]propyl)-3,7- dihydro-1H-purine-2,6-dione 209

30.5 m/z 483[MH]⁺ RT 3.64 min. 3-butyl-8-chloro-1-{3-[3-(1- phenylcyclobutyl)-1,2,4-oxadiazol- 5-yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione

Example 210 3-Butyl-8-chloro-1-[3-(3-{[4-(methyloxy)phenyl]methyl}-1,2,4-oxadiazol-5-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

Prepared using a method analogous to that used for Example 93, except an additional final purification step using HPLC was employed. Yield 6.0 mg.

LC/MS: m/z 473 [MH]⁺, RT 3.27 min.

The following compounds (Table 12) were prepared using a method analogous to that for Example 96, using the appropriate amidoxime [with the exception that for Example 211 the scale was 0.12 mmol instead of 0.15 mmol; for Example 216 the crude product was stirred in EtOH (0.75 ml) with 2M NaOH (0.5 ml) overnight prior to the usual EtOAc/HCl workup and MDAP; Example 218 was isolated as an impurity from the preparation of Example 219 and was separated from it by HPLC; for Examples 221, 222 and 223 the pH during aqueous workup was adjusted to approximately 5 prior to extraction; additionally Example 223 was further purified by silica SPE (2 g, DCM-MeOH 40:1 then 20:1) after MDAP].

TABLE 12 Yield Example Structure (mg) LC/MS 211

23.8 m/z 537 [MH]⁺ RT 3.83 min 3-butyl-8-chloro-1-(3-{3-[1-(2,4- dichlorophenyl)cyclopropyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 212

39.5 m/z 507 [MH]⁺ RT 3.58 min 3-butyl-8-chloro-1-[3-(3-{[5-chloro-2- (methyloxy)phenyl]methyl}-1,2,4- oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 213

35.8 m/z 529 [MH]⁺ RT 3.41 min 1-(3-{3-[4,5-bis(methyloxy)-2,3- dihydro-1H-inden-1-yl]-1,2,4- oxadiazol-5-yl}propyl)-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6- dione 214

9.7 m/z 511 [MH]⁺ RT 3.63 min 3-butyl-8-chloro-1-(3-{3-[(2,5- dichlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 215

18.0 m/z 446 [MH]⁺ RT 3.15 min 3-butyl-8-chloro-1-(3-{3-[(1-methyl-1H- pyrrol-2-yl)methyl]-1,2,4-oxadiazol-5- yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 216

15.5 m/z 464 [MH]⁺ RT 2.94 min 3-butyl-8-chloro-1-(3-{3-[(4-methyl- 1,3-thiazol-2-yl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 217

33.5 m/z 479 [MH]⁺ RT 3.35 min 3-butyl-8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 218

4.6 m/z 545 [MH]⁺ RT 3.71 min 3-butyl-8-chloro-1-(3-{3-[(2,3,6- trichlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 219

17.7 m/z 545 [MH]⁺ RT 3.79 min 3-butyl-8-chloro-1-(3-{3-[(2,4,5- trichlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 220

17.8 m/z 455 [MH]⁺ RT 3.49 min 3-butyl-8-chloro-1-(3-{3-[(E)-2- phenylethenyl]-1,2,4-oxadiazol-5- yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 221

39.2 m/z 467 [MH]⁺ RT 3.24 min 3-butyl-8-chloro-1-(3-{3-[(4-chloro-1H- pyrazol-1-yl)methyl]-1,2,4-oxadiazol- 5-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 222

27.0 m/z 452 [MH]⁺ RT 2.56 min 3-butyl-8-chloro-1-{3-[3-(4- morpholinylmethyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 223

23.6 m/z 444 [MH]⁺ RT 2.92 min 3-butyl-8-chloro-1-{3-[3-(2- pyridinylmethyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 224

38.8 m/z 495 [MH]⁺ RT 3.43 min 3-butyl-8-chloro-1-(3-{3-[(2-chloro-6- fluorophenyl)methyl]-1,2,4-oxadiazol- 5-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 225

27 m/z 491 [MH]⁺ RT 3.31 min 3-butyl-8-chloro-1-[3-(3-{[3-fluoro-4- (methyloxy)phenyl]methyl)-1,2,4- oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione

The following compounds (Table 13) were prepared using a method analogous to that for Example 114, using the appropriate amidoxime [with the exception that Example 226 was conducted on half the scale of Example 114 and during workup the aqueous phase was neutralised prior to extraction; Example 227 was conducted on half the scale of Example 114 and the crude product stirred with 2M NaOH (0.5 ml) in EtOH (1 ml) for 5 h prior to workup and MDAP; for Example 232 0.185 ml (0.5 mmol) of 21% NaOEt was used].

TABLE 13 Yield Example Structure (mg) LC/MS 226

20 m/z 444 [MH]⁺ RT 2.74min 3-butyl-8-chloro-1-{3-[3-(3- pyridinylmethyl)-1,2,4-oxadiazol-5- yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 227

7.2 m/z 448 [MH]⁺ RT 3.13 min 3-butyl-8-chloro-1-(3-{3-[(5-methyl-3- isoxazolyl)methyl]-1,2,4-oxadiazol-5- yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 228

47.4 m/z 519 [MH]⁺ RT 3.71 min 3-butyl-8-chloro-1-{3-[3-(diphenylmethyl)- 1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro- 1H-purine-2,6-dione 229

36.7 m/z 429 [MH]⁺ RT 3.36 min 3-butyl-8-chloro-1-[3-(3-phenyl-1,2,4- oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 230

41.1 m/z 447 [MH]⁺ RT 3.42 min 3-butyl-8-chloro-1-{3-[3-(4-fluorophenyl)- 1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro- 1H-purine-2,6-dione 231

36.7 m/z 469 [MH]⁺ RT 3.60 min 3-butyl-8-chloro-1-{3-[3-(5-chloro-2- thienyl)-1,2,4-oxadiazol-5-yl]propyl)-3,7- dihydro-1H-purine-2,6-dione 232

47.0 m/z 503 [MH]⁺ RT 3.14 min 1-[3-(3-{[3,4- bis(methyloxy)phenyl]methyl}-1,2,4- oxadiazol-5-yl)propyl]-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6-dione 233

29.2 m/z 533 [MH]⁺ RT 3.62 min 3-butyl-8-chloro-1-(3-{3- [(pentafluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 234

29.8 m/z 500 [MH]⁺ RT 3.01 min N-[4-({5-[3-(3-butyl-8-chloro-2,6-dioxo- 2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]- 1,2,4-oxadiazol-3- yl}methyl)phenyl]acetamide 235

37.7 m/z 511 [MH]⁺ RT 3.65 min 3-butyl-8-chloro-1-[3-(3-{[4- (trifluoromethyl)phenyl]methyl}-1,2,4- oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 236

47.5 m/z 493 [MH]⁺ RT 3.69 min 3-butyl-8-chloro-1-{3-[3-(2- naphthalenylmethyl)-1,2,4-oxadiazol-5- yl]propyl)-3,7-dihydro-1H-purine-2,6- dione

Example 237 3-Butyl-8-chloro-1-(3-{3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

Synthesised by a method analogous to that for Example 126 with the exception that a further 2 equivalents of 21% sodium ethoxide (0.11 ml) was used, the extra heating time was 20 min. and the product was isolated by filtration followed by trituration with hot MeOH. Yield 14.5 mg.

LC/MS: m/z 499 [MH]⁺, RT 2.78 min.

The following compounds (Table 14) were prepared by a method analogous to that for Example 18 [with the exception that Examples 238-243 were all synthesised on a scale starting from 50 mg of 8-chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione; Examples 241, 243, 245, 246 and 247 were additionally purified by MDAP following aminopropyl SPE; Example 242 was additionally purified by recrystallisation from MeOH following aminopropyl SPE; for Example 248, 128 mg (1.2 mmol) of sodium carbonate was used; during workup the aqueous phase was adjusted to pH6 prior to extraction; and the product was purified by MDAP then by further HPLC; for Example 241 solids which precipitated during workup were combined with the EtOAc extracts prior to SPE].

TABLE 14 Example Structure Yield (mg) LC/MS 238

36.0 m/z 480 [MH]⁺ RT 3.24 min 4-({4-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-1H- purin-1-yl)propyl]-1H-pyrazol- 1-yl}methyl)benzonitrile 239

7.6 m/z 536 [MH]⁺ RT 3.03 min 8-chloro-1-(3-{1-[(1-methyl-2- oxo-1,2-dihydro-6- quinolinyl)methyl]-1H-pyrazol- 4-yl}propyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 240

34.0 m/z 526 [MH]⁺ RT 3.11 min 8-chloro-1-(3-{1-[(3-methyl-2- oxo-2,3-dihydro-1,3- benzoxazol-6-yl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 241

26.2 m/z 473 [MH]⁺ RT 3.38 min 8-chloro-1-(3-{1-[(3- fluorophenyl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 242

16.2 m/z 520 [MH]⁺ RT 3.12 min methyl 3-({4-[3-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)propyl]-1H-pyrazol-1- yl}methyl)-4- isothiazolecarboxylate 243

21.0 m/z 512 [MH]⁺ RT 3.36 min 1-{3-[1-(1,3-benzothiazol-2- ylmethyl)-1H-pyrazol-4- yl]propyl)-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 244

65.0 m/z 523, 525 [Cl isotopes MH⁺] RT 3.77 min 8-chloro-1-(3-{1-[(2,6- dichlorophenyl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 245

35.0 m/z 491 [MH]⁺ RT 3.61 min 8-chloro-1-(3-{1-[(3,4- difluorophenyl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 246

17.0 m/z 541 [MH]⁺ RT 3.76 min 8-chloro-1-[3-(1-{[4-fluoro-3- (trifluoromethyl)phenyl]methyl)- 1H-pyrazol-4-yl)propyl]-3- pentyl-3,7-dihydro-1H-purine 2,6-dione 247

27.0 m/z 507 [MH]⁺ RT 3.73 min 8-chloro-1-(3-{1-[(3-chloro-4- fluorophenyl)methyl]-1H- pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 248

11.4 m/z 456 [MH]⁺ RT 3.13 min 8-chloro-3-pentyl-1-{3-[1-(2- pyridinylmethyl)-1H-pyrazol-4- yl]propyl}-3,7-dihydro-1H- purine-2,6-dione

Example 249 8-Chloro-1-(3-{1-[(4-chlorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.123 mmol) in dry DMF (1.5 ml) was stirred with sodium carbonate (75 mg, 0.708 mmol) and 4-chlorobenzyl bromide (150 mg, 0.73 mmol) at 40° C. for 18 h. The mixture was partitioned between EtOAc and water, the organic phase washed with brine, dried and evaporated. The product was purified by normal phase chromatography on silica (Companion System, EtOAc—cyclohexane gradient) giving an oil (44 mg). This was stirred in degassed, dry DMF (1 ml) with tetrakis(triphenylphosphine)palladium(0) (19 mg) and morpholine (0.072 ml) under nitrogen for 6 h. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated and purified by the usual aminopropyl SPE procedure. Yield 21.0 mg.

LC/MS: m/z 489 [MH⁺], RT 3.59 min.

The following compounds (Table 15) were prepared by a method analogous to that for Example 23 [with the exception that for Example 250 a second portion of Pd(PPh₃)₄ was added after 5 h, stirring was continued overnight, and final purification was achieved by HPLC; for Example 252 required additional purification by MDAP; Example 257 required additional purification by recrystallisation from MeOH; Example 258 required additional purification by trituration with MeOH].

TABLE 15 Yield Example Structure (mg) LC/MS 250

7.3 m/z 447 [MH]⁺ RT 3.06 min 8-chloro-1-{3-[1-(1,2,4-oxadiazol-3- ylmethyl)-1H-pyrazol-4-yl]propyl)-3- pentyl-3,7-dihydro-1H-purine-2,6-dione 251

23.7 m/z 469 [MH]⁺ RT 3.49 min 8-chloro-1-(3-{1-[(4- methylphenyl)methyl]-1H-pyrazol-4- yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 252

29.0 m/z 460 [MH]⁺ RT 3.10 min 8-chloro-1-(3-{1-[(5-methyl-3- isoxazolyl)methyl]-1H-pyrazol-4- yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 253

56.0 m/z 485 [MH]⁺ RT 3.41 min 8-chloro-1-[3-(1-{[3- (methyloxy)phenyl]methyl)-1H-pyrazol-4- yl)propyl]-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 254

47.0 m/z 523 [MH]⁺ RT 3.61 min 8-chloro-3-pentyl-1-[3-(1-{[3- (trifluoromethyl)phenyl]methyl}- 1H- pyrazol-4-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 255

44.0 m/z 469 [MH]⁺ RT 3.54 min 8-chloro-1-(3-{1-[(2- methylphenyl)methyl]-1H-pyrazol-4- yl}propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 256

51.0 m/z 480 [MH]⁺ RT 3.32 min 3-({4-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]- 1H-pyrazol-1-yl}methyl)benzonitrile 257

36.7 m/z 483 [MH]⁺ RT 3.66 min 8-chloro-1-(3-{1-[(3,5- dimethylphenyl)methyl]-1H-pyrazol-4- yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 258

21.2 m/z 522 [MH]⁺ RT 3.09 min 8-chloro-3-pentyl-1-[3-(1-([4-(1H-1,2,4- triazol-1-yl)phenyl]methyl}-1H-pyrazol-4- yl)propyl]-3,7-dihydro-1H-purine-2,6- dione

Example 259 8-Chloro-3-pentyl-1-[3-(1-pentyl-1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) and sodium carbonate (32 mg, 0.3 mmol) in dry DMF (1.5 ml) was heated with 1-iodopentane (238 mg, 1.2 mmol) in the microwave reactor at 120° C. for 25 min. After cooling the mixture was degassed and stirred with tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.0346 mmol) and morpholine (0.2 ml) for 7 h. A further 20 mg of Pd(PPh₃)₄ was then added and stirring continued overnight. The mixture was stirred with EtOAc and 2M HCl for 1 h and the organic phase separated and evaporated. The product was purified by aminopropyl SPE (5 g) washing with MeOH-THF (1:1), then MeOH, and eluting the product with DCM-MeOH (1:1) containing 5% added AcOH to give the title compound (25 mg).

LC/MS: m/z 435 [MH]⁺, RT 3.65 min.

The following compounds (Table 16) were prepared by a method analogous to that for Example 259 [with the exception that the compounds were purified by MDAP and for Example 261 the total heating time in the microwave reactor was 50 min].

TABLE 16 Example Structure Yield (mg) LC/MS 260

15.1 m/z 451 [MH]⁺ RT 3.21 min ethyl {4-[3-(5-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-1H-pyrazol-1-yl}acetate 261

1.34 m/z 421 [MH]⁺ RT 3.48 min 8-chloro-1-(3-[1-(2-methylpropyl)-1H- pyrazol-4-yl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 262

0.32 m/z 409 [MH]⁺ RT 2.79 min 8-chloro-1-{3-[1-(2-hydroxyethyl)-1H- pyrazol-4-yl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 263

9.6 m/z 404 [MH]⁺ RT 3.12 min {4-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-1H-pyrazol-1-yl}acetonitrile

Example 264 8-Chloro-3-pentyl-1-{3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol), sodium carbonate (42 mg, 0.4 mmol) and (2-iodoethyl)benzene (0.174 ml, 1.2 mmol) were heated together in dry DMF (1 ml) under microwave irradiation at 120° C. for 25 min. Tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and morpholine (0.174 ml) were added and the mixture stirred for 6 h. Further quantities (46 mg and 0.174 ml) of these reagents were added and stirring continued for a further 60 h. Workup and purification as for the examples in Table 16 gave the title compound (15.5 mg).

LC/MS: m/z 469 [MH]⁺, RT 3.60 min.

Example 265 8-Chloro-3-pentyl-1-(3-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol), sodium carbonate (159 mg, 1.5 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (127 mg, 0.75 mmol) were heated together in dry DMF (2 ml) at 80° C. for 65 h. Tetrabutylammonium iodide (55 mg, 0.15 mmol) was added and heating continued for another 18 h. A further quantity of 1-(2-chloroethyl)pyrrolidine hydrochloride (127 mg, 0.75 mmol) was added and the mixture heated by microwaves at 120° C., then a 3^(rd) aliquot of 1-(2-chloroethyl)pyrrolidine hydrochloride (100 mg) was added, with a further 25 min at 120° C. in the microwave. The mixture was partitioned between water and EtOAc, the organic phase separated, washed with brine and evaporated. This material was partitioned between EtOAc and 2M HCl. The separated aqueous phase was basified to pH9, saturated with NaCl and extracted with EtOAc (×2). The extracts were evaporated and the residue (28 mg) stirred in dry degassed DMF (1.5 ml) with tetrakis(triphenylphosphine)palladium(0) (50 mg) and morpholine (0.2 ml) for 6 h. The mixture was partitioned between EtOAc and 2M HCl, the aqueous phase filtered, extracted twice with EtOAc and evaporated to dryness. The residue was purified by the aminopropyl SPE procedure, followed by MDAP to yield the title compound (1.9 mg).

LC/MS: m/z 462 [MH]⁺, RT 2.46 min.

Example 266 8-Chloro-1-(3-{1-[(5-chloro-2-thienyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

To 8-chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry THF (1 ml) at −78° C., under nitrogen, was added potassium t-butoxide (1M in THF, 0.15 ml), followed by 2-chloro-5-(chloromethyl)thiophene (25 mg, 0.15 mmol). Stirring was continued at −78° C. for 15 min, then at room temperature for 1 h and finally at 60° C. for 18 h. The solution was degassed and morpholine (0.13 ml) and tetrakis(triphenylphosphine)palladium(0) (35 mg) added and stirring continued for 6 h. Further quantities (0.2 ml morpholine, 50 mg Pd(PPh₃)₄) were added and stirring continued overnight. Worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by the standard aminopropyl SPE procedure followed by MDAP yielding title compound as a white solid (5.1 mg).

LC/MS: m/z 495 [MH]⁺, RT 3.68 min.

Example 267 8-Chloro-3-pentyl-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione acetate

8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.124 mmol) in dry degassed THF (1.5 ml) was stirred with tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and morpholine (0.108 ml) under nitrogen for 5 h. The mixture was partitioned between EtOAc and 0.5M citric acid and the organic phase separated. Two further EtOAc extractions were performed and the combined organics were evaporated and the product purified by aminopropyl SPE (2 g), loading and washing with THF-MeOH (1:1) then washing with MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Yield 28.3 mg.

LC/MS: m/z 365 [M]⁺, RT 2.89 min.

Example 268 8-Chloro-3-hexyl-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-hexyl-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-hexyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-d lone (100 mg, 0.322 mmol), cesium carbonate (126 mg, 0.387 mmol) and 2-chloroethanol (29.8 mg, 0.37 mmol) in dry DMF (3 ml) were heated together under nitrogen at 55° C. for 42 h. The cooled mixture was degassed thoroughly and stirred with tetrakis(triphenylphosphine)palladium(0) (74 mg) and morpholine (0.28 ml) for 5 h. The reaction was worked up by partition between EtOAc and 2M HCl, the organic phase being separated and evaporated. The residue was loaded onto an aminopropyl SPE cartridge (5 g) in THF-MeOH (1:1), washed with the same solvent, then with neat MeOH, and the product eluted with DCM-MeOH (1:1) containing AcOH (2.5% rising to 5%). The product thus obtained was further purified by MDAP to afford the title compound (38 mg).

LC/MS: m/z 315 [MH]⁺, RT 2.79 min.

b) 8-Chloro-3-hexyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

To 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (226 mg, 1 mmol) and sodium carbonate (117 mg, 1.1 mmol) in dry DMF (7 ml) was added 1-iodohexane (223 mg, 1.05 mmol). The mixture was stirred and heated at 50° C. for 2 days. After cooling, the mixture was partitioned between EtOAc and water, the organic phase washed with brine, dried over Na₂SO₄ and evaporated. The crude product was recrystallised from EtOAc-cyclohexane (1:2). Yield 146 mg.

LC/MS: m/z 311 [MH]⁺, RT 3.12 min.

The following compounds (Table 17) were prepared by a method analogous to that for Example 268, except for Example 270 the scale was reduced to 75 mg (0.243 mmol) of the precursor 8-chloro-3-(3-cyclopropylpropyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione.

TABLE 17 Yield Example Structure Precursor (mg) LC/MS 269

8-chloro-3-(4- methylpentyl)-7-(2- propen-1-yl)-3,7- dihydro-1H-purine- 2,6-dione 37 m/z 315 [MH]⁺ RT 2.74 min 8-chloro-1-(2-hydroxyethyl)- 3-(4-methylpentyl)-3,7- dihydro-1H-purine-2,6-dione 270

8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen-1-yl)- 3,7-dihydro-1H- purine-2,6-dione 26 m/z 313 [MH]⁺ RT 2.58 min 8-chloro-3-(3- cyclopropylpropyl)-1-(2- hydroxyethyl)-3,7-dihydro- 1H-purine-2,6-dione

The intermediates were prepared according to the method of Example 268b, except that 8-chloro-3-(3-cyclopropylpropyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione was purified by silica SPE (5 g) eluting with EtOAc-cyclohexane (2:3).

Scale Yield Intermediate Name (mmol) Alkylating agent (mg) LC/MS

8-chloro-3-(4- methylpentyl)-7- (2-propen-1-yl)- 3,7-dihydro-1H- purine-2,6-dione 1 1-bromo-4- methylpentane (173 mg) 210 m/z 311 [MH]⁺ RT 3.08 min

8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen-1- yl)-3,7-dihydro- 1H-purine-2,6- dione 0.662 3-cyclopropylpropyl 4- methylbenzenesulfonate (170 mg) 125 m/z 309 [MH]⁺ RT 2.93 min

Example 271 3-Butyl-8-chloro-1-{3-[5-(phenylmethyl)-1,3,4-oxadiazol-2-yl]propyl}-3,7-dihydro-1H-purine-2,6-dione

To 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (99 mg, 0.35 mmol) in dry DMF (2 ml) was added cesium carbonate (137 mg, 0.42 mmol) followed by a solution in dry DMF (1 ml) of 2-(3-chloropropyl)-5-(phenylmethyl)-1,3,4-oxadiazole (99 mg, 0.42 mmol). The mixture was stirred under nitrogen and heated at 55° C. for 2.5 h then stirred at room temperature overnight. The mixture was degassed by repeatedly evacuating and admitting nitrogen and then tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmol) and morpholine (0.305 ml, 3.5 mmol) were added and stirring was continued for 5 h EtOAc and 2M HCl were added and the mixture stirred for 20 min then filtered. The organic phase was separated and evaporated, and the product was purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1) then with MeOH and eluting the acidic product with DCM-MeOH (1:1) containing 5% added AcOH. The product thus obtained was purified further by MDAP to yield the title compound (92 mg).

LC/MS: m/z 443 [MH]⁺, RT 3.18 min.

The following compounds (Table 18) were prepared by a method analogous to that for Example 271, with the exception that Example 279 was further purified by HPLC.

TABLE 18 Xanthine Alkylating Yield Example Product structure precursor agent (mg) LC/MS 272

3-butyl-8- chloro-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (99 mg) 2-[(2-chloro-4- fluorophenyl) methyl]-5-(3- chloropropyl)- 1,3,4- oxadiazole (121 mg) 90 m/z 495 [MH]⁺ RT 3.34 min 3-butyl-8-chloro-1-(3-{5- [(2-chloro-4- fluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl)propyl)-3,7-dihydro-1H- purine-2,6-dione 273

8-chloro-3- pentyl-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (104 mg) 2-(3- chloropropyl)- 5- (phenylmethyl)- 1,3,4- oxadiazole (99 mg) 98 m/z 457 [MH]⁺ RT 335 min 8-chloro-3-pentyl-1-{3-[5- (phenylmethyl)-1,3,4- oxadiazol-2-yl]propyl}- 3,7-dihydro-1H-purine- 2,6-dione 274

8-chloro-3- pentyl-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (104 mg) 2-[(2-chloro-4- fluorophenyl) methyl]-5-(3- chloropropyl)- 1,3,4- oxadiazole (121 mg) 98 m/z 509 [MH]⁺ RT 3.52 min 8-chloro-1-(3-{5-[(2- chloro-4- fluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl}propyl)-3-pentyl-3,7- dihydro-1H-purine-2,6- dione 275

8-chloro-3- pentyl-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (104 mg) 2-(3- chloropropyl)- 5-[(2,4- difluorophenyl) methyl]-1,3,4- oxadiazole (111 mg) 43 m/z 493 [MH]⁺ RT 3.40 min 8-chloro-1-(3-{5-[(2,4- difluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl}propyl)-3-pentyl-3,7- dihydro-1H-purine-2,6- dione 276

8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen- 1-yl)-3,7- dihydro-1H- purine-2,6- dione (108 mg) 2-(3- chloropropyl)- 5- (phenylmethyl)- 1,3,4- oxadiazole (99 mg) 95 m/z 469 [MH]⁺ RT 3.34 min 8-chloro-3-(3- cyclopropylpropyl)-1-{3- [5-(phenylmethyl)-1,3,4- oxadiazol-2-yl]propyl}- 3,7-dihydro-1H-purine- 2,6-dione 277

8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen- 1-yl)-3,7- dihydro-1H- purine-2,6- dione (108 mg) 2-[(2-chloro-4- fluorophenyl) methyl]-5-(3- chloropropyl)- 1,3,4- oxadiazole (121 mg) 99 m/z 521 [MH]⁺ RT 3.51 min 8-chloro-1-(3-{5-[(2- chloro-4- fluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl}propyl)-3-(3- cyclopropylpropyl)-3,7- dihydro-1H-purine-2,6- dione 278

8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen- 1-yl)-3,7- dihydro-1H- purine-2,6- dione (108 mg) 2-(3- chloropropyl)- 5-[(2,4- difluorophenyl) methyl]-1,3,4- oxadiazole (111 mg) 49 m/z 505 [MH]⁺ RT 3.40 min 8-chloro-3-(3- cyclopropylpropyl)-1-(3- {5-[(2,4- difluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 279

3-butyl-8- chloro-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (99 mg) 2-(3- chloropropyl)- 5-[(2,4- difluorophenyl) methyl]-1,3,4- oxadiazole (111 mg) 38.9 m/z 479 [MH]⁺ RT 3.31 min 3-butyl-8-chloro-1-(3-{5- [(2,4- difluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl}propyl)-3,7-dihydro-1H- purine-2,6-dione Synthesis of Chloropropyl 1,3,4-oxadiazole Intermediates from Table 18

-   2-[(2-chloro-4-fluorophenyl)methyl]-5-(3-chloropropyl)-1,3,4-oxadiazole -   2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole -   2-(3-chloropropyl)-5-(phenylmethyl)-1,3,4-oxadiazole

Diacyl hydrazines (500 mg, synthesis below) were stirred in dry toluene (4 ml) and phosphorus oxychloride (4 ml) was added. The mixtures were heated at 90° C. for 2 h then allowed to cool and the solvents evaporated. The residues were dissolved in dry toluene, evaporated and then partitioned between EtOAc and aqueous NaHCO₃. The organic phases were washed with brine, dried over Na₂SO₄ and evaporated to give the required oxadiazoles as colourless oils. These were not purified further but reacted directly with the xanthines as above.

Yield Diacyl hydrazine Oxadiazole product (mg) LC/MS

4-chloro-N′- (phenylacetyl)butanohydrazide

2-(3-chloropropyl)-5- (phenylmethyl)-1,3,4- oxadiazole 446 m/z 237 [MH]⁺ RT 2.94 min

4-chloro-N′-[(2-chloro-4- fluorophenyl)acetyl]butanohydrazide

2-[(2-chloro-4- fluorophenyl)methyl]-5- (3-chloropropyl)-1,3,4- oxadiazole 405 m/z 289 [MH]⁺ RT 3.17 min

N-chloro-N′-[(2,4- difluorophenyl)acetyl]butanohydrazide

2-(3-chloropropyl)-5- [(2,4- difluorophenyl)methyl]- 1,3,4-oxadiazole 333 m/z 273 [MH]⁺ RT 3.03 min

Preparation of 4-chloro-N′-(phenylacetyl)butanohydrazide

To 4-chlorobutyryl chloride (1.12 ml, 10 mmol) in dry DCM (10 ml) was added, dropwise, over 40 min, a mixture of phenylacetic hydrazide (1.5 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (40 ml) at room temperature. A dense white precipitate formed. After a further 20 min. 2M HCl (30 ml) was added and the title compound (white solid) was filtered off, washed with water and dried (2.24 g).

LC/MS: m/z 255 [MH]⁺, RT 2.20 min.

Preparation of 4-chloro-N′-[(2-chloro-4-fluorophenyl)acetyl]butanohydrazide

(i) A solution of 2-chloro-4-fluorophenylacetyl chloride (10 mmol) in dry DCM (15 ml) was added over 20 min to a mixture of t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (20 ml). After stirring for a further 2 h, the mixture was washed with 1M HCl then with aqueous NaHCO₃. A white solid precipitated at this point, which was filtered off, washed with water and DCM then dried to yield 1,1-dimethylethyl 2-[(2-chloro-4-fluorophenyl)acetyl]hydrazinecarboxylate (1.94 g).

(ii) This compound (1.92 g, 6.34 mmol) was suspended in dioxan (2 ml) and 4M HCl in dioxan (5 ml) was added. A dense white precipitate formed. After 1 h the mixture was partitioned between EtOAc and saturated aqueous NaHCO₃ and the organic phase washed with brine, dried (Na₂SO₄) and evaporated giving 2-(2-chloro-4-fluorophenyl)acetohydrazide as a white solid (1.07 g).

(iii) A mixture of 2-(2-chloro-4-fluorophenyl)acetohydrazide (909 mg, 4.5 mmol) and DIPEA (0.817 ml, 4.7 mmol) in dry DCM (65 ml) was added over 20 min to 4-chlorobutyryl chloride (0.505 ml, 4.5 mmol) in dry DCM (5 ml). After 1.5 h, 2M HCl was added and the precipitated 4-chloro-N′-[(2-chloro-4-fluorophenyl)acetyl]butanohydrazide was filtered off, washed with water and dried (1.24 g).

LC/MS: m/z 307 [MH]⁺, RT 2.61 min.

Preparation of 2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole

(i) A solution of 2,4-difluorophenylacetyl chloride (10 mmol) in dry DCM (15 ml) was added over 10 min. to a mixture of t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (20 ml). After stirring for 1.5 h the mixture was washed with 1M HCl then with aqueous NaHCO₃. The organic phase was evaporated to afford 1,1-dimethylethyl 2-[(2,4-difluorophenyl)acetyl]hydrazinecarboxylate as a white solid.

(ii) 1,1-dimethylethyl 2-[(2,4-difluorophenyl)acetyl]hydrazinecarboxylate (10 mmol) in dioxan (5 ml) was stirred with 4M HCl in dioxan (8 ml) for 1.5 h. The mixture was partitioned between EtOAc and saturated aqueous NaHCO₃ and the organic phase washed with brine, dried (Na₂SO₄) and evaporated. Reaction was incomplete so the residue was stirred again with 4M HCl in dioxan (10 ml) for 2.5 h. Workup as previously gave 2-(2,4-difluorophenyl)acetohydrazide as a solid (570 mg).

(iii) A mixture of 2-(2,4-difluorophenyl)acetohydrazide (570 mg, 3.06 mmol) and DIPEA (0.553 ml, 3.2 mmol) in dry DCM (30 ml) was added to 4-chlorobutyryl chloride (0.343 ml, 3.06 mmol) in dry DCM (5 ml) over 15 min. An immediate white precipitate formed. After stirring for 1 h, 2M HCl (20 ml) was added and the solid 2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole was filtered off, washed with water and dried (726 mg).

LC/MS: m/z 291 [MH]⁺, RT 2.45 min.

Example 280 3-Butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione

3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.354 mmol) and 4-(3-phenyl-5-isoxazolyl)-1-butanol (77 mg, 0.355 mmol) were dissolved in dry THF (4 ml) under nitrogen. A solution of dibenzyl azodicarboxylate (94%, 224 mg, 0.708 mmol) in dry THF (2 ml) was added. The mixture was cooled to 0° C. and a solution of triphenylphosphine (185 mg, 0.708 mmol) in dry THF (1 ml) was added. The mixture was stirred for 20 min at 0° C. then at room temperature overnight. The mixture was degassed then stirred with morpholine (0.308 ml) and tetrakis(triphenylphosphine)palladium(0) (82 mg) for 4.5 h. A further 60 mg of tetrakis(triphenylphosphine)palladium(0) was added and stirring continued overnight. The reaction was worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Further purification by MDAP afforded the title compound (56 mg).

LC/MS: m/z 442 [MH]⁺, RT 3.59 min.

b) 4-(3-Phenyl-5-isoxazolyl)-1-butanol

To N-hydroxybenzenecarboximidoyl chloride (622 mg, 4 mmol) in dry DCM (6 ml) was added 5-hexyn-1-ol (431 mg, 4.4 mmol). The mixture was cooled to 0° C. under nitrogen as triethylamine (0.612 ml, 4.4 mmol) was added dropwise over 10 min. Stirred for a further 20 min at 0° C. then at room temperature overnight. The mixture was washed with water and the organic phase evaporated. The product was purified by silica SPE (20 g) eluting with EtOAc-cyclohexane (1:2, then 3:1) to give a white waxy solid (443 mg).

LC/MS: m/z 218 [MH]⁺, RT 2.74 min.

Example 281 3-Butyl-8-chloro-1-{3-[3-(Phenylmethyl)-5-isoxazolyl]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-5-isoxazolyl]propyl}-3,7-dihydro-1H-purine-2,6-dione

Prepared analogously to 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione (Example 280) using half the molar quantities, starting from 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.177 mmol) and 3-[3-(phenylmethyl)-5-isoxazolyl]-1-propanol (38.4 mg, 0.177 mmol). Yield 24.2 mg,

LC/MS: m/z 442 [MH]⁺, RT 3.43 min.

b) 3-[3-(Phenylmethyl)-5-isoxazolyl]-1-propanol

Synthesised as with 4-(3-phenyl-5-isoxazolyl)-1-butanol, using N-hydroxy-2-phenylethanimidoyl chloride (253 mg, 1.5 mmol) and 4-pentyn-1-ol (139 mg, 1.65 mmol). Yield 61 mg of pale yellow oil.

LC/MS: m/z 218 [MH]⁺, RT 2.62 min.

Example 282 3-Butyl-8-chloro-1-{3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]propyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]propyl}-3,7-dihydro-1H-purine-2,6-dione

Prepared by the method of 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione starting from 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.354 mmol) and 3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]-1-propanol (83.5 mg, 0.354 mmol) except that a 2^(nd) aliquot of 250 mg of tetrakis(triphenylphosphine)palladium(0) was added during the deprotection step. Yield 19.6 mg

LC/MS: m/z 461 [MH]⁺, RT 3.75 min.

b) 3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]-1-propanol

To 3-phenyl-1,2,4-oxadiazole-5(2H)-thione (178 mg, 1 mmol) in dry THF (3 ml) was added DIPEA (0.174 ml, 1 mmol) and 3-bromo-1-propanol (139 mg, 1 mmol). Stirring was continued for 65 h then the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na₂SO₄) and evaporated to give title compound as an oil (235 mg).

LC/MS: m/z 237 [MH]⁺, RT 2.94 min.

Example 283 3-Butyl-8-chloro-1-{2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethyl}-3,7-dihydro-1H-purine-2,6-dione

Prepared by a method analogous to that used for Example 270 (3-Butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-2,6-dione) starting from 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (141 mg, 0.5 mmol) and 2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethanol (111 mg, 0.5 mmol). A single portion of tetrakis(triphenylphosphine)palladium(0) (232 mg) was used in the deprotection step, however, stirring being continued for 6 h. Purification by aminopropyl SPE followed by MDAP afforded the title compound as a white solid (33.1 mg).

LC/MS: m/z 447 [MH]⁺, RT 3.67 min.

b) 2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethanol

The title compound was obtained in a similar manner to 3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]-1-propanol, from 2-bromoethanol, after a reaction time of 24 h and purification by silica SPE (ethyl acetate-cyclohexane 1:1). Yield 176 mg.

LC/MS: m/z 223 [MH]⁺, RT 2.98 min.

Example 284 3-Butyl-8-chloro-1-(2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethyl)-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-(2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethyl)-3,7-dihydro-1H-purine-2,6-dione

3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (64.4 mg, 0.228 mol), 2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethanol (50 mg, 0.228 mmol) and dibenzyl azodicarboxylate (136 mg, 0.456 mmol) were stirred in dry THF (3 ml) at 0° C. as triphenylphosphine (119 mg, 0.456 mmol) in dry THF (1 ml) was added dropwise. The mixture was stirred at 0° C. for 10 min. then at room temperature for 2 overnight periods. It was thoroughly degassed and stirred with morpholine (0.2 ml) and tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.046 mmol) for 5 h. A further 53 mg of the catalyst was then added and stirring continued overnight. The reaction was worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Further purification by MDAP afforded the title compound (11.8 mg).

LC/MS: m/z 444 [MH]⁺, RT 3.12 min.

b) 2-{[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethanol

3-(Phenylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (140 mg, 0.505 mmol) in dry DMF (2 ml) was stirred with ethanolamine (0.25 ml) for 1.5 h. The mixture was partitioned between EtOAc and water, the organic phase washed with water, brine, dried (Na₂SO₄) and evaporated to give a white waxy solid (87 mg).

LC/MS: m/z 220 [MH]⁺, RT 2.22 min.

Example 285 3-Butyl-8-chloro-1-(2-{[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethyl)-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-(2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethyl)-3,7-dihydro-1H-purine-2,6-dione

3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.531 mmol) and 2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethanol (125 mg, 0.530 mmol) in dry THF (4 ml) were cooled to 0° C. and dibenzyl azodicarboxylate (94%, 336 mg, 1.06 mmol) in dry THF (2 ml) was added followed by triphenylphosphine (278 mg, 1.06 mmol). The mixture was stirred at 0° C. for 15 min. then at room temperature for 2 overnight periods. Morpholine (1 g) and tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.216 mmol) were added to the degassed solution, and after 5 h a further 100 mg of Pd(PPh₃)₄ was added and stirring continued for 3 overnight periods. The reaction was worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Further purification by MDAP afforded the title compound afforded title compound (26 mg).

LC/MS: m/z 461 [MH]⁺, RT 3.47 min.

b) 2-{[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethanol

To 3-(phenylmethyl)-1,2,4-oxadiazole-5(2H)-thione (384 mg, 2 mmol) in dry THF (5 ml) was added DIPEA (0.348 ml, 2 mmol) and 2-bromoethanol (250 mg, 2 mmol). The mixture was stirred at room temperature overnight and then partitioned between EtOAc and 1M HCl. The organic phase was washed with brine, dried, evaporated and purified by silica SPE (10 g) eluting with EtOAc-cyclohexane (1:2) to give title compound (315 mg) as a colourless oil.

LC/MS: m/z 237 [MH]⁺, RT 2.74 min.

Example 286 3-Butyl-8-chloro-1-{[3-(3-Phenylpropyl)-1,2,4-oxadiazol-5-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{[3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione

Ethyl (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (66 mg, 0.2 mmol) and (1Z)-N-hydroxy-4-phenylbutanimidamide (39 mg, 0.22 mmol) were stirred in dry ethanol (1 ml) with ethanolic sodium ethoxide (21% wt. solution, 0.111 ml, 0.3 mmol) and heated under microwave irradiation at 140 C for 10 min. The cooled mixture was partitioned between ethyl acetate and 2M hydrochloric acid, the organic phase separated and evaporated. The product was purified by MDAP to give the title compound as a solid (31.5 mg).

LC/MS: m/z 443 [MH]⁺, RT 3.56 min.

b) Ethyl (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate

3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 5.31 mmol) and cesium carbonate (1.903 g, 5.84 mmol) were stirred together in dry DMF (25 ml). Ethyl bromoacetate (0.648 ml, 5.84 mmol) was added and the mixture was stirred at 55 C overnight. The cooled mixture was degassed using nitrogen and stirred with tetrakis(triphenylphosphine)palladium(0) (1 g) and morpholine (3.73 ml) for 4.5 h. The mixture was partitioned between ethyl acetate (80 ml) and 2M HCl (50 ml). The organic phase was washed with 3×80 ml brine, filtered, dried over Na₂SO₄ and evaporated. The product was purified by aminopropyl SPE (20 g), washing with THF-MeOH (1:1), then neat MeOH and eluting the product with DCM-MeOH (1:1) containing acetic acid (2.5% rising to 5%), which gave pure title compound (1.16 g).

LC/MS: m/z 329 [MH]⁺, RT 2.87 min.

Example 287 3-Butyl-8-chloro-1-{[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione

Synthesised by a method analogous to that for Example 286, starting from (1Z)-N-hydroxy-3-phenylpropanimidamide. Yield 22.6 mg.

LC/MS: m/z 429 [MH]⁺, RT 3.43 min.

Example 288 3-Butyl-8-chloro-1-{2-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]ethyl}-3,7-dihydro-1H-purine-2,6-dione

Synthesised by a method analogous to that for Example 286, starting from (1Z)-N-hydroxy-3-phenylpropanimidamide and ethyl 3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate. Yield 23.3 mg.

LC/MS: m/z 443 [MH]⁺, RT 3.40 min.

Example 289 Ethyl 3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate

Synthesised as for ethyl (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate starting from ethyl 3-bromopropanoate (0.749 ml, 5.84 mmol), except that, after the initial overnight heating period, further ethyl 3-bromopropanoate (1.5 ml) was added, heating was resumed for a further 4 h, then a further portion of cesium carbonate (1.903 g), followed 2 h later by a third portion of ethyl 3-bromopropanoate (1.5 ml) were added. Heating at 55 C was then continued for a second overnight period before workup and deprotection as above. Yield 0.404 g.

LC/MS: m/z 343 [MH]⁺, RT 2.90 min.

The following compounds (Table 19) were prepared by a method analogous to that for Example 3, with any modification noted in the method A-F.

TABLE 19 Yield Example Structure (mg) LC/MS Method 290

10 m/z 495 [MH]⁺ RT 3.30 min A 1-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-1H-naphtho[2,3-d]imidazole- 4,9-dione, sodium salt 291

24 m/z 414 [MH]⁺ RT 3.72 min A 8-chloro-1-[3-(1H-indol-3-yl)propyl]-3- pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 292

27 m/z 437 [MH]⁺ RT 2.41 min A 5-amino-1-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-2-methyl-1H-imidazole-4- carboxamide, sodium salt 293

21 m/z 382 [MH]⁺ RT 2.86min A 8-chloro-1-[3-(2-oxo-1- pyrrolidinyl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 294

9 m/z 487 [MH]⁺ RT 3.15 min A 8-chloro-1-{3-[2,5-dioxo-4- (phenylmethyl)-1-imidazolidinyl]propyl}- 3-pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 295

39 m/z 538 [MH]⁺ RT 3.46 min A 2-({[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]amino}carbonyl)-1,2-dihydro 1-acenaphthylenecarboxylic acid, sodium salt 296

18 m/z 381 [MH]⁺RT 2.33 min A 1-[3-(3-amino-1H-1,2,4-triazol-5- yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 297

22 m/z 369 [MH]⁺ RT 3.2 min A 8-chloro-3-pentyl-1-[3-(tetrahydro-2- furanyl)propyl]-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 298

8 m/z 446 [MH]⁺ RT 2.55 min A 1-[3-(2-amino-6-methyl-9H-purin-9- yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 299

21 m/z 431 [MH]⁺ RT 3.9 min A 1-[3-(1-benzothien-2-yl)propyl]-8- chloro-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 300

31 m/z 508 [MH]⁺ RT 3.56 min A N-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-2,2-diphenylacetamide, sodium salt 301

22 m/z 382 [MH]⁺ RT 2.76 min A 8-chloro-1-[3-(5-oxo-2- pyrrolidinyl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 302

33 m/z 455 [MH]⁺ RT 4.01 min A 8-chloro-1-{3-[5-(methyloxy)-1- naphthalenyl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 303

5 m/z 405 [MH]⁺ RT 3.71 min A 8-chloro-1-{3-[2- (methyloxy)phenyl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 304

15 m/z 393 [MH]⁺ RT 3.7 min A 8-chloro-1-[3-(2-fluorophenyl)propyl]-3- pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 305

15 m/z 425 [MH]⁺ RT 4.04 min A 8-chloro-1-[3-(1-naphthalenyl)propyl]- 3-pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 306

13 m/z 400 [MH]⁺ RT 3.51 min A 3-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]benzonitrile, sodium salt 307

19 m/z 451 [MH]⁺ RT 4.06 min A 1-[3-(4-biphenylyl)propyl]-8-chloro-3- pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 308

30 m/z 453 [MH]⁺ RT 3.2 min A 8-chloro-1-{3-[4- (methylsulfonyl)phenyl]propyl}-3- pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 309

2 m/z 376 [MH]⁺ RT 2.41 min A 8-chloro-3-pentyl-1-[3-(4- pyridinyl)propyl]-3,7-dihydro-1H-purine- 2,6-dione 310

46 m/z 566 [MH]⁺ RT 4.23 min A 8-chloro-1-[3-(2,3-diphenyl-1H-indol-1- yl)propyl]-3-pentyl-3,7-dihydro-1H- purine-2,6-dione, sodium salt 311

1 m/z 513 [MNH4]⁺ RT 3.38 min B 2-(3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-2H-naphtho[2,3- d][1,2,3]triazole-4,9-dione 312

21 m/z 542 [MH]⁺ RT 3.62 min B 8-chloro-1-(3-{6-[(4- chlorophenyl)amino]-9H-purin-9- yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 313

7 m/z 381 [MH]⁺ RT 2.33 min B 1-[3-(3-amino-1H-1,2,4-triazol-5- yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 314

17 m/z 463 [MH]⁺ RT 3.24 min B 1-{4-[3,4-bis(methyloxy)phenyl]-4- oxobutyl}-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 315

2 m/z 582 [MH]⁺ RT 3.79 min B 8-chloro-1-{4-oxo-4-(1-(phenylsulfonyl)- 1H-indol-2-yl]butyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 316

14 m/z 415 [MH]⁺ RT 2.45 min B 1-[3-(1H-benzimidazol-2-yl)propyl]-8- chloro-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 317

5 m/z 433 [MH]⁺ RT 2.69 min C 1-[3-(7-amino-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)propyl]-8-chloro-3- pentyl-3,7-dihydro-1H-purine-2,6-dione 318

2 m/z 508 [MH]⁺ RT 4.11 min D 1-[3-(5-bromo-1-methyl-1H-indol-2- yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 319

17 m/z 443 [MH]⁺ RT 2.59 min E 8-chloro-1-[3-(1-ethyl-1H- benzimidazol-2-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 320

25 m/z 443 [MH]⁺ RT 2.61 min F 8-chloro-1-[3-(5,6-dimethyl-1H- benzimidazol-2-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione

Method A: Analogous to that for Example 3

Method B: Similar to Method A, except material was purified using autopreparative HPLC after purification by aminopropyl SPE.

Method C: Similar to Method A, except material was purified by washing with water after purification by aminopropyl SPE.

Method D: Similar to Method A, except material was purified by MDAP after purification by aminopropyl SPE.

Method E: Similar to Method A, except material was purified by SCX SPE after initial purification using aminopropyl SPE.

Method F: Similar to Method A, except material was purified using preparative HPLC using a Zorbax Phenyl column.

Example 321 8-Chloro-1-[3-(ethyloxy)ethyl]-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-[3-(ethyloxy)ethyl]-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione

To a greenhouse tube equipped with a stirrer was added caesium carbonate (85 mg, 0.26 mmol), followed by a solution of 8-chloro-7-(2-propen-1-yl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione (69 mg, 0.22 mmol) in dry DMF (1 ml) and then a solution of 1-bromo-3-(ethyloxy)ethane (60 mg, 0.39 mmol) in dry DMF (1 ml). The mixture was heated to 80° C. for 5 h under nitrogen, then allowed to cool to room temperature for 16 h. The reaction mixture was concentrated using a vacuum centrifuge. THF (2.5 ml) was added to the mixture, followed by Pd(PPh₃)₄ (30 mg, 0.026 mmol) and morpholine (190 uL, 2.2 mmol) and the mixture stirred at rt under nitrogen for 72 h. The mixture was partitioned between 2N HCl (2 ml) and chloroform (4 ml), the organic layer separated using a hydrophobic frit, and the aqueous layer extracted with chloroform (2×4 ml). Combined organic layers were concentrated under reduced pressure then loaded in 1:1 DCM/MeOH onto an aminopropyl SPE (5 g), washing with 1:1 DCM/MeOH and eluting with 20% to 80% acetic acid in 1:1 DCM/MeOH. Solvent was removed under reduced pressure to afford the title compound as a solid (70 mg, 93%).

¹H NMR (MeOD) δ: 1.11 (t, 3H, J=7 Hz), 3.51 (q, 2H, J=7 Hz), 3.64 (t, 2H, J=6 Hz), 4.18 (t, 21-1, J=6 Hz), 4.73 (q, 2H, J=9 Hz).

LC/MS: m/z 341 [MH]⁺, RT 2.72 min.

b) 8-Chloro-7-(2-propen-1-yl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.62 mmol) in dry DMF (50 ml) was stirred with sodium carbonate (980 mg, 9.25 mmol) and 1,1,1-trifluoro-2-iodoethane (1.2 g, 5.71 mmol) at room temperature for 18 h under nitrogen. The mixture was heated at 50° C. for 6 h then cooled to rt and stirred for a further 10 h. The mixture was heated at 120° C. for 4 h, further 1,1,1-trifluoro-2-iodoethane (426 mg, 2.03 mmol) added, and the reaction mixture heated at 120° C. for a further 3 h. The reaction mixture was concentrated under reduced pressure.

A further amount of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.8 g, 16.8 mmol) in dry DMF (125 ml) was stirred with sodium carbonate (2.5 g, 23.1 mmol) and 1,1,1-trifluoro-2-iodoethane (4.1 g, 19.5 mmol) and the reaction mixture heated at 120° C. for 16 h under nitrogen. This reaction mixture was combined with the previous crude material and concentrated under reduced pressure. The residue was triturated with DCM, the mixture filtered, and the filtrate concentrated under reduced pressure then dissolved in DCM (20 ml). 10 ml of this material was purified by silica chromatography using a 100 g Silica column, eluting the title compound with a suitable gradient of ethyl acetate/cyclohexane. The remaining 10 ml was purified using a Silica RediSep cartridge (130 g) on a Companion, eluting the title compound with a suitable gradient of ethyl acetate/cyclohexane. Fractions containing the title compound from both purification modes were combined and concentrated under reduced pressure to give the title compound as a white solid (1.6 g, 22% overall yield).

LC/MS: m/z 309 [MH]⁺, RT 2.59 min.

Example 322 8-Chloro-1-[3-(2,6-dichlorophenyl)propyl]-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, sodium salt

To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (40 mg, 0.14 mmol) in dry DMF (0.25 ml) was added caesium carbonate (49 mg, 0.15 mmol) followed by a solution of 2-(3-bromopropyl)-1,3-dichlorobenzene (54 mg, 0.20 mmol) in dry DMF (0.25 ml). The mixtures were stirred at 60° C. for 16 h, then Pd(PPh₃)₄ (16 mg, 0.014 mmol) added, followed by morpholine (118 uL, 1.4 mmol) and the mixtures stirred for a further 16 h. Solvent was removed using a vacuum centrifuge and the sample dissolved in DMSO (0.25 ml) then loaded onto a C18 SPE (5 g). 2N NaOH (0.5 ml) was added and a suitable gradient of ammonia/water/MeCN used to elute the product. The title compound was isolated as a solid (52 mg, 83%).

¹H NMR (DMSO-d₆) δ: 0.84 (t, 3H, J=7 Hz), 1.18-1.36 (m, 4H), 1.55-1.69 (m, 2H), 1.69-1.85 (m, 2H), 2.78-2.89 (m, 2H), 3.85 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), 7.23 (dd, 1H, J=9 and 7 Hz), 7.41 (d, 2H, J=7 Hz).

LC/MS: m/z 445 [MH]⁺, RT 4.05 min.

The following compounds (Table 20) were prepared using a method analogous to that for the Example 322, from the corresponding alkyl halides:

TABLE 20 Yield Example Structure (mg) LC/MS: Method 323

57 m/z 505 [MH]⁺ RT 3.14 min A N-({[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]amino}carbonyl)-N- (phenylmethyl)glycine, sodium 324

16 m/z 530 [MH]⁺ RT 3.36 min A 8-chloro-1-[3-(9H- dibenzo[c,f][1,2,4]triazolo[4,3-a]azepin-3- yl)propyl]-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione, sodium 325

18 m/z 430 [MH]⁺ RT 3.12 min A 8-chloro-1-[3-(1-oxo-1,3-dihydro-2H- isoindol-2-yl)propyl]-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione, sodium salt 326

18 m/z 467 [MH]⁺ RT 2.99 min A 8-chloro-3-pentyl-1-(3-[1,2,4]triazolo[3,4- a]phthalazin-3-ylpropyl)-3,7-dihydro-1H- purine-2,6-dione, sodium salt 327

30 m/z 464 [MH]⁺ RT 4.03 min A 1-[3-(9H-carbazol-9-yl)propyl]-8-chloro-3- pentyl-3,7-dihydro-1H-purine-2,6-dione, sodium salt 328

42 m/z 396 [MH]⁺ RT 3.17 min A 8-chloro-1-[3-(4-methyl-1,3-thiazol-5- yl)propyl]-3-pentyl-3,7-dihydro-1H-purine 2,6-dione, sodium salt 329

31 m/z 477 [MH]⁺ RT 2.83 min A 7-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-yl)propyl]-1,3- dimethyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 330

50 m/z 439 [MH]⁺ RT 3.56 min A 1-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-yl)propyl]-1H- indole-3-carbonitrile, sodium salt 331

10 m/z 527 [MH]⁺ RT 4.3 min A 8-chloro-1-{3-[3-ethyl-6-(trifluoromethyl)- 1-benzothien-2-yl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium 332

5 m/z 495 [MH]⁺ RT 2.21 min A 3-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-yl)propyl]-1-[3-(3- pyridinyl)propyl]pyridinium 333

45 m/z 501 [MH]⁺ RT 4.01 min A 1-[4,4-bis(4-fluorophenyl)butyl]-8-chloro- 3-pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 334

33 m/z 494 [MH]⁺ RT 3.69 min A N-(3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-yl)propyl)-4- biphenylcarboxamide, sodium salt 335

18 m/z 376 [MH]⁺ RT 2.5 min A 8-chloro-3-pentyl-1-[3-(3- pyridinyl)propyl]-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 336

39 m/z 431 [MH]⁺ RT 3.13 min A 8-chloro-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione, sodium salt 337

4 m/z 432 [MH]⁺ RT 2.53 min B 1-[3-(6-amino-9H-purin-9-yl)propyl]-8- chloro-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 338

1 m/z 444 [MH]⁺ RT 3.39 min C 8-chloro-1-[3-(1,3-dioxo-1,3-dihydro-2H- isoindol-2-yl)propyl]-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione 339

3 m/z 416 [MH]⁺ RT 2.87 min C 8-chloro-1-[3-(1,3-dihydro-2H-isoindol-2- yl)propyl]-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 340

8 m/z 431 [MH]⁺ RT 2.83 min D 8-chloro-1-[3-(6-methyl[1,2,4]triazolo[4,3- b]pyridazin-3-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 341

3 m/z 414 [MH]⁺ RT 2.64 min E 8-chloro-1-[3-(6-methyl[1,2,4]triazolo[4,3- b]pyridazin-3-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione

Method A: Analogous to that for Example 3

Method B: Similar to Method A, except after concentration by vacuum centrifuge, material was partitioned between 2M HCl and DCM, the aqueous layer isolated then purified using C18 SPE in the manner described in Method A.

Method C: Similar to Method A, except after concentration by vacuum centrifuge, material was partitioned between 2M HCl and DCM, and the product was isolated from the organic layer after autopreparative HPLC.

Method D: Similar to Method A, except product was isolated using aminopropyl SPE.

Method E: Similar to Method A, except material was further purified on a phenyl HPLC using a suitable gradient of water/MeOH/MeCN/TFA, then autopreparative HPLC, using a suitable gradient of water/acetonitrile.

The following compounds (Table 21) were prepared using a method analogous to that for Example 142, from the corresponding acids and (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide.

TABLE 21

Example Name Compound: R1 = LC/MS 342 3-butyl-8-chloro-1-[3-(5-methyl- 1,2,4-oxadiazol-3-yl)propyl]-3,7- dihydro-1H-purine-2,6-dione

m/z 367 [MH]⁺ RT 2.7 min 343 3-butyl-8-chloro-1-{3-[5- (cyclopropylmethyl)-1,2,4- oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione

m/z 407 [MH]⁺ RT 3.11 min 344 3-butyl-8-chloro-1-{3-[5-(3- methylphenyl)-1,2,4-oxadiazol- 3-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione

m/z 443 [MH]⁺ RT 3.47 min 345 3-butyl-8-chloro-1-{3-[5-(4- methylphenyl)-1,2,4-oxadiazol- 3-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione

m/z 443 [MH]⁺ RT 3.34 min 346 3-butyl-8-chloro-1-(3-{5-[2-(2,3- difluorophenyl)ethyl]-1,2,4- oxadiazol-3-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione

m/z 493 [MH]⁺ RT 3.47 min 347 3-butyl-8-chloro-1-(3-{1,2,4- oxadiazol-3-yl)propyl]-3,7- dihydro-1H-purine-2,6-dione

m/z 381 [MH]⁺ RT 2.9 min 348 3-butyl-1-[3-(5-butyl-1,2,4- oxadiazol-3-yl)propyl]-8-chloro- 3,7-dihydro-1H-purine-2,6-dione

m/z 409 [MH]⁺ RT 3.27 min 349 3-butyl-8-chloro-1-[3-(5- cyclopentyl-1,2,4-oxadiazol-3- yl)propyl]-3,7-dihydro-1H-purine- 2,6-dione

m/z 421 [MH]⁺ RT 3.29 min 350 3-butyl-8-chloro-1-[3-(5-{[4- (dimethylamino)phenyl]methyl}- 1,2,4-oxadiazol-3-yl)propyl]-3,7- dihydro-1H-purine-2,6-dione

m/z 486 [MH]⁺ RT 3.24 min 351 3-butyl-8-chloro-1-{3-[5-(3- thienylmethyl)-1,2,4-oxadiazol-3- yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione

m/z 449 [MH]⁺ RT 3.24 min 352 3-butyl-8-chloro-1-{3-[5-(1H- indol-3-ylmethyl)-1,2,4- oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione

m/z 482 [MH]⁺ RT 3.29 min

Example 353 3-Butyl-8-chloro-1-(2-{[4-(2-thienyl)phenyl]oxy}ethyl)-3,7-dihydro-1H-purine-2,6-dione

A microwave vial containing a magnetic stirrer bar was charged with 2-thienylboronic acid (16 mg, 0.125 mmol), 1-{2-[(4-bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.113 mmol), aqueous sodium carbonate (1 ml, 1M solution) and dimethoxyethane (1 ml). This mixture was degassed with nitrogen and then Pd(PPh₃)₂Cl₂ (4 mg, 5.6×10⁻⁶ mol) was added. The reaction mixture was capped and heated at 140° C. in a microwave for 15 min (pressure reached 7 bar). The crude reaction mixture was acidified with HCl (2M, 1.5 ml), washed with chloroform (2×1 ml) and the phases separated. The combined organics were evaporated and the crude product purified by MDAP to afford the title compound (10 mg).

LC/MS: m/z 445 [MH]⁺, RT 3.76 min

Example 354 3-Butyl-8-chloro-1-(2-{[4-(4-methyl-2-thienyl)Phenyl]oxy}ethyl)-3,7-dihydro-1H-purine-2,6-dione

A microwave vial containing a magnetic stirrer bar was charged with (4-methyl-2-thienyl)boronic acid (18 mg, 0.125 mmol), 1-{2-[(4-bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.113 mmol), aqueous sodium carbonate (1 ml, 1M solution) and dimethoxyethane (1 ml). This mixture was degassed with nitrogen and then Pd(PPh₃)₂Cl₂ (4 mg, 0.0056 mmol) was added. The reaction mixture was capped and heated at 140° C. in a microwave for 15 min (pressure reached 7 bar). The crude reaction mixture was acidified with HCl (2M, 1.5 ml), washed with chloroform (2×1 ml) and the phases separated. The combined organics were evaporated and the crude product purified by MDAP to afford the title compound (17 mg).

LC/MS: m/z 459 [MH]⁺, RT 3.9 min

Example 355 1-{2-[(4-Bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione a) 1-{2-[(4-Bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione

1-{2-[(4-Bromophenyl)oxy]ethyl}-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.3 g, 4.8 mmol) was stirred in a mixture of nitrogen degassed DCM (40 ml) and AcOH (4 ml). Tetrakis(triphenylphosphine)palladium (1.1 g, 0.896 mmol) and phenylsilane (5.9 ml, 48 mmol) were added and the mixture stirred at rt for 2 h. This was then evaporated and the residue triturated with a mixture of diethylether:cyclohexane (1:2) to afford the title compound (1.02 g, 49%) as a white solid.

LC/MS: m/z 441/443 [MH]⁺, RT 3.6 min

b) 1-{2-[(4-bromophenyl)oxy]ethyl}-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.8 g, 9.8 mmol) in dry DMF (50 ml) was added Cs₂CO₃ (6.4 g, 19.6 mmol) followed by 2-bromoethyl 4-bromophenyl ether (3.6 g, 13 mmol). The mixture was heated at 80° C. for 17 h and then allowed to cool. The reaction mixture was evaporated and the crude product partitioned between EtOAc and HCl (2N). The organic phase was separated and washed with brine, dried (MgSO₄) and evaporated to give the crude product. This was purified by silica SPE (50 g), eluting with cyclohexane:ethylacetate (10:1 to 1:1) to afford the title compound as a cream coloured solid (2.9 g, 62%).

LC/MS: m/z 381/483 [MH]⁺, RT 3.87 min.

Example 356 1,1′-(1,4-Butanediyl)bis(3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione)

a) 1,1′-(1,4-Butanediyl)bis(3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione)

1,1′-(1,4-Butanediyl)bis[3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione] (24 mg, 0.039 mmol) was stirred in a mixture of nitrogen degassed DCM (2 ml) and AcOH (0.2 ml). Tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol) and phenylsilane (42 uL, 0.39 mmol) were added and the mixture stirred at rt for 2 h. This was then evaporated and the crude product purified by reverse phase chromatography (5-95% gradient, H₂O: CH₃CN) to afford the title compound (2 mg).

LC/MS: m/z 539 [MH]⁺, RT 3.33 min

b) 1,1′-(1,4-Butanediyl)bis[3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione]

3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (60 mg, 0.212 mmol) in dry DMF (1 ml) was added Cs₂CO₃ (207 mg, 0.636mol) followed by 1,4-diiodobutane (16 uL, 0.106 mmol). The mixture was heated at 80° C. for 17 h and then allowed to cool. The reaction mixture was partitioned between DCM and HCl (2M). The organic phase was separated and washed with brine, dried (MgSO₄) and evaporated to give the crude product. This was purified by MDAP to afford the title compound as a cream coloured solid (24 mg).

LC/MS: m/z 619 [MH]⁺, RT 3.95 min.

The following compounds (Table 22) were prepared using a method analogous to that for Example 356.

TABLE 22 Example Name Structure Yield LC/MS: 357 3-butyl-1-[5-(3-butyl-8- chloro-2,6-dioxo-2,3,6,9- tetrahydro-1H-purin-1- yl)pentyl]-8-chloro-3,7- dihydro-1H-purine-2,6- dione

2.4 mg m/z 553 [MH]⁺ RT 3.43 min 358 3-butyl-1-[7-(3-butyl-8- chloro-2,6-dioxo-2,3,6,9- tetrahydro-1H-purin-1- yl)heptyl]-8-chloro-3,7- dihydro-1H-purine-2,6- dione

3.6 m/z 581 [MH]⁺ RT 3.72 min

Example 359 8-Chloro-1-[2-(ethyloxy)ethyl]-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (84 mg, 0.25 mmol) in DMF (1 ml) was treated with caesium carbonate (163 mg, 0.5 mmol) and 1-bromo-2-(ethyloxy)ethane (42 mg, 0.275 mmol). The mixture was heated at 80° C. for 4 h and then cooled.

The reaction mixture was degassed with nitrogen and then treated with morpholine (220 uL) and tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol) and stirred for 4 h. The reaction mixture was partitioned between chloroform and HCl (2M). The organic phase was separated and evaporated. The crude product was loaded on to an aminopropyl SPE. The non acidic impurities were eluted with a mixture of DCM and MeOH and the desired product eluted with 10% AcOH in DCM. Evaporation afforded the title compound (77 mg).

LC/MS: m/z 369 [MH]⁺, RT 1.96 min.

Example 360 8-Chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (40 mg, 0.09 mmol) in DMF (3 ml) was treated with potassium carbonate (15 mg, 0.11 mmol) and 1-iodopropane (19 mg, 0.11 mmol). The mixture was heated at 40° C. for 3 h then at 70° C. for a further 3 h. The mixture was cooled and degassed by the successive application of vacuum and nitrogen gas. The mixture was then treated with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and morpholine (0.1 ml, 1.2 mmol) and then stirred overnight. The mixture was evaporated and partitioned between chloroform (2 ml) and water (2 ml). The aqueous phase was extracted with further chloroform (2 ml) and the combined organics evaporated and the residue dissolved in methanol (2 ml). The solution was applied to a 1 g aminopropyl SPE and eluted with methanol and then with 5% acetic acid in methanol. Product-containing fractions were pooled and evaporated and the product further purified by MDAP to reveal 8-chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1.4 mg) as a white solid.

LC/MS: m/z 430 [MH]⁺, RT 2.84 min.

b) 8-Chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A suspension of N-hydroxy-2-pyridinecarboximidamide (1.15 g, 8.4 mmol) in anhydrous THF (20 ml) was treated with sodium methoxide (0.38 g, 7.0 mmol) and the mixture stirred for 5 min. The mixture was treated with ethyl 5-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoate (2 g, 5.6 mmol) and the stirred for about 5 min until all the material had dissolved. The mixture was then sealed and heated in a microwave at 120° C. for 15 min then cooled and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous phase was extracted with further ethyl acetate (50 ml) and the combined organics dried (MgSO₄), filtered and evaporated. The product was purified by flash chromatography using a gradient elution from 1:9 ethyl acetate/cyclohexane to ethyl acetate to reveal 8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1.49 g) as a white solid.

LC/MS: m/z 428 [MH]⁺, RT 2.70 min.

Similarly prepared was 8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using ethyl 4-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanoate.

LC/MS: m/z 463 [MH]⁺, RT 3.09 min.

c) Ethyl 5-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoate

A solution of 8-chloro-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 28 mmol) in DMF (10 ml) was treated with potassium carbonate (4.8 g, 35 mmol) and ethyl 5-bromopentanoate (6.5 g, 31 mmol) and then heated to 70° C. for 3 h, cooled and evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic phase was dried (MgSO₄), filtered and evaporated and the crude intermediate dissolved in dichloromethane (90 ml), treated with trifluoroacetic acid (17 ml) and the mixture stirred at ambient temperature overnight. Toluene (50 ml) was added and the mixture evaporated to dryness. The product was purified by flash chromatography using a gradient elution from cyclohexane to ethyl acetate to reveal 8.65 g of ethyl 5-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoate as a white solid.

LC/MS: m/z 355 [MH]⁺, RT 2.75 min.

Similarly prepared was ethyl 4-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanoate.

LC/MS: m/z 341 [MH]⁺, RT 2.61 min.

d) 8-Chloro-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-dihydro-1H-purine-2,6-dione

To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5 g, 22.1 mmol) in DMF (80 ml) was added 2-2-(trimethylsilyl)ethoxymethyl chloride (4.3 ml, 24.2 mmol) and sodium carbonate (2.6 g, 24.2 mmol). After stirring at room temperature overnight further 2-2-(trimethylsilyl)ethoxymethyl chloride (4.3 ml, 24.2 mmol) and sodium carbonate (1.3 g, 12.1 mmol) were added and stirring continued for 2 h. The reaction mixture was then partitioned between 5% LiCl aq and ethyl acetate. The organic extract was separated, washed with brine, dried (MgSO₄) and concentrated. Purification by Biotage™ chromatogratphy using a silica cartridge eluting 1:4-1:2 ethyl acetate/cyclohexane afforded the title compound (3.14 g, 40%).

m/z 374 [MNH₄ ⁺]

The following compounds (Table 23) were prepared by a method analogous to that for Example 360, from 8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione and the appropriate alkylating agent.

TABLE 23

Example R = Name Yield (mg) m/z RT (min) 361

8-chloro-1-{4-[3-(2- pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 2.5 388 2.37 362

8-chloro-3-methyl-1-{4- [3-(2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.7 402 2.53 363

8-chloro-3-ethyl-1-{4-[3- (2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.4 416 2.66 364

8-chloro-3- (phenylmethyl)-1-{4-[3- (2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.3 478 3.09 365

8-chloro-3-(2- methylpropyl)-1-{4-[3- (2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 2.0 444 2.99 366

8-chloro-3-(3- methylbutyl)-1-{4-[3-(2- pyridinyl)-1,2,4- oxadiazol-5-yl]butyl)- 3,7-dihydro-1H-purine- 2,6-dione 1.6 458 3.21 367

8-chloro-3-(2- phenylethyl)-1-{4-[3-(2- pyridinyl)-1,2,4- oxadiazol-5-yl]butyl)- 3,7-dihydro-1H-purine- 2,6-dione 2.1 492 3.18 368

8-chloro-1-{4-[3-(2- pyndinyl)-1,2,4- oxadiazol-5-yl]butyl}-3- (4,4,4-trifluorobutyl)-3,7- dihydro-1H-purine-2,6- dione 2.1 498 3.07 369

8-chloro-1-{4-{3-(2- pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}-3- [2-(1H-pyrrol-1-yl)ethyl]- 3,7-dihydro-1H-purine- 2,6-dione 2.7 481 2.89 370

8-chloro-3-[2- (phenyloxy)ethyl]-1-{4- [3-(2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.7 508 3.11 371

8-chloro-1-{4-[3-(2- pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}-3- [3-(1H-pyrrol-1- yl)propyl]-3,7-dihydro- 1H-purine-2,6-dione 2.1 495 3.01 372

8-chloro-3-(2-propen-1- yl)-1-{4-[3-(2-pyridinyl)- 1,2,4-oxadiazol-5- yl]butyl)-3,7-dihydro-1H- purine-2,6-dione 1.3 428 2.73 373

8-chloro-3-[3- (methyloxy)propyl]-1-{4- [3-(2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.0 460 2.65

The following compounds (Table 24) were prepared by a method analogous to that for Example 360, from 8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione and the appropriate alkylating agent.

TABLE 24

Yield RT Example R = Name (mg) m/z (min) 374

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 2.5 423 2.71 375

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3- methyl-3,7-dihydro-1H-purine- 2,6-dione 1.7 437 2.92 376

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-ethyl- 3,7-dihydro-1H-purine-2,6- dione 1.4 451 3.06 377

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3- propyl-3,7-dihydro-1H-purine- 2,6-dione 2.2 465 3.22 378

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 2.6 493 3.54 379

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(2- hydroxyethyl)-3,7-dihydro-1H- purine-2,6-dione 2.7 467 2.72 380

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(3- hydroxypropyl)-3,7-dihydro- 1H-purine-2,6-dione 2.0 481 2.77 381

8-chloro-1-(3-{3-((2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(4- hydroxybutyl)-3,7-dihydro-1H- purine-2,6-dione 1.4 495 2.80 382

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl)propyl)-3- (phenylmethyl)-3,7-dihydro- 1H-purine-2,6-dione 1.6 513 3.43 383

8-chloro-3-(cyclopropylmethyl)- 1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 1.8 477 3.30 384

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl)propyl)-3-(2- methylpropyl)-3,7-dihydro-1H- purine-2,6-dione 3.5 479 3.36 385

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl)propyl)-3-(3- methylbutyl)-3,7-dihydro-1H- purine-2,6-dione 3.1 493 3.53 386

8-chloro-3-(cyclobutylmethyl)- 1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 2.2 491 3.45 387

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(2- phenylethyl)-3,7-dihydro-1H- purine-2,6-dione 2.4 527 3.50 388

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl)propyl)-3-(3- methyl-2-buten-1-yl)-3,7- dihydro-1H-purine-2,6-dione 3.1 491 3.46 389

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(4,4,4- trifluorobutyl)-3,7-dihydro-1H- purine-2,6-dione 3.0 533 3.39 390

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7-dihydro-1H- purine-2,6-dione 2.7 519 3.34 391

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl)propyl)-3-[2- (1H-pyrrol-1-yl)ethyl]-3,7- dihydro-1H-purine-2,6-dione 2.0 516 3.27 392

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl)propyl)-3-[2- 1H-purine-2,6-dione 1.6 543 3.44 393

8-chloro-1-(3-{3-((2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7-dihydro- 1H-purine-2,6-dione 2.8 495 3.11 394

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-[2- (methyloxy)ethyl]-3,7-dihydro- 1H-purine-2,6-dione 2.6 481 2.98 395

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-(2- propen-1-yl)-3,7-dihydro-1H- purine-2,6-dione 3.1 463 3.17 396

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-[3- (methyloxy)propyl)-3,7- dihydro-1H-purine-2,6-dione 2.1 495 3.04 397

8-chloro-3-cyclopentyl-1-(3-{3- [(2,4-difluorophenyl)methyl]- 1,2,4-oxadiazol-5-yl}propyl)- 3,7-dihydro-1H-purine-2,6- dione 2.5 491 3.52

Example 398 1-[3-(3-Bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-(3-bromophenyl)-propan-1-ol (1.627 g, 7.56 mmol) in THF (65 ml) was treated with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.04 g, 6.87 mmol) under nitrogen. PPh₃ (2.164 g, 8.25 mmol) was added to the stirred mixture after 2 min and after a further 6 min DBAD (1.9 g, 8.25 mmol) was added in one portion. The mixture was stirred for 2.5 h and then left to react for 16 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (794 mg, 0.69 mmol) was added and the mixture degassed once more. Morpholine (6 ml, 68.8 mmol) was added and the mixture was stirred under nitrogen for 6 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The residue was taken up into MeOH and purified by passing down an aminopropyl SPE, the product eluted with 2-5% AcOH/MeOH. The title compound was obtained as an off-white solid (2.48 g, 79%).

LC/MS: m/z 455, 453 [MH]⁺, RT 3.85 min.

Example 399 8-Chloro-1-{2-[(3-hydroxyphenyl)oxy]ethyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione and Example 400 8-chloro-1-(2-{[3-({2-[(3-hydroxyphenyl)oxy]ethyl}oxy)phenyl]oxy}ethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 2-(2-hydroxyethyl)-resorcinol (1.156 g, 7.5 mmol) in THF (60 ml) was treated with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.016 g, 6.79 mmol) under nitrogen. PPh₃ (2.138 g, 8.15 mmol) was added to the stirred mixture after 4 min and after a further 8 min DBAD (1.88 g, 8.16 mmol) was added in one portion. The mixture was stirred for 1 h 50 min and then left to react for 16 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (785 mg, 0.68 mmol) was added and the mixture degassed once more. Morpholine (5.9 ml, 67.7 mmol) was added and the mixture was stirred under nitrogen for 4.5 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO₄) and concentrated. The residue was taken up into MeOH and purified by passing it down an aminopropyl SPE, the product gradient elution with 2-5% AcOH/MeOH. The fractions containing product were evaporated to give a pale yellow foam (2.39 g) and a pale yellow gum (213 mg). The foam was dissolved in dichloromethane (50 ml) and passed through a hydrophobic frit. The solution was evaporated and dried in vacuo to give 8-chloro-1-{2-[(3-hydroxyphenyl)oxy]ethyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione as a white solid (1.919 g, containing 15% 8-chloro-1-(2-([3-({2-[(3-hydroxyphenyl)oxy]ethyl}oxy)phenyl]oxy)ethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione).

The gum was purified by MDAP to give 8-chloro-1-{2-[(3-hydroxyphenyl)oxy]ethyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione as a white solid (126 mg).

LC/MS: m/z 393 [MH]⁺, RT 3.23 min as well as 8-chloro-1-(2-{[3-({2-[(3-hydroxyphenyl)oxy]ethyl}oxy)phenyl]oxy}ethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione as a pale yellow solid (38 mg).

LC/MS: m/z 529 [MH]⁺, RT 3.62 min.

The following compounds (Table 25) were prepared using a method analogous to that for 8-chloro-1-(2-[(3-hydroxyphenyl)oxy]ethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione above, from the corresponding alcohol.

TABLE 25 Yield Example Structure (mg) LC/M: 401

58 m/z 391 [MH]⁺ RT 3.38 min 8-chloro-1-[3-(4-hydroxyphenyl)propyl]-3-pentyl- 3,7-dihydro-1H-purine-2,6-dione 402

12 m/z 525 [MH]⁺ RT 4.07 min 8-chloro-1-[3-(4-{[3-(4- hydroxyphenyl)propyl]oxy}phenyl)propyl]-3- pentyl-3,7-dihydro-1H-purine-2,6-dione

Example 403 8-Chloro-1-(3-{3-[(3-chlorophenyl)oxy]phenyl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

1-[3-(3-Bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.22 mmol) was dissolved in dioxan (0.75 ml). Copper (1) iodide (9 mg, 0.05 mmol), N,N-dimethylglycine hydrochloride (9 mg, 0.06 mmol), cesium carbonate (215 mg, 0.66 mmol) and 3-chlorophenol (52 mg, 0.4 mmol) were added to the solution. The mixture was heated under microwave irradiation at 200° C. for 10 min, followed by another 10 min at 200° C. after which the cooled mixture was filtered and the residue washed with EtOAc and MeOH. The filtrate and washings were combined and evaporated under reduced pressure to leave a red/brown solid. The solid was partitioned between DCM and water. The phases were separated by hydrophobic frit and the organic evaporated under reduced pressure to leave a solid. The solid was purified by MDAP to give the title compound as a yellow solid/gum (27 mg, 24%).

LC/MS: m/z 501 [MH]⁺, RT 4.25 min.

Example 404 8-Chloro-3-pentyl-1-{3-[3-(phenyloxy)phenyl]propyl}-3,7-dihydro-1H-purine-2,6-dione

1-[3-(3-Bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.22 mmol), copper (1) iodide (4 mg, 0.02 mmol), N,N-dimethylglycine hydrochloride (9 mg, 0.06 mmol) cesium carbonate (144 mg, 0.44 mmol) and phenol (31 mg, 0.33 mmol) were placed in dioxan (0.44 ml). Then the mixture was heated in the microwave at 150° C. for 3.3 min, then further quantities of cesium carbonate (72 mg, 0.22 mmol), copper (1) iodide (6 mg, 0.03 mmol) and dioxan (0.44 ml) were added to the mixture and heated in the microwave at 170° C. for 10 min, followed by another 10 min at 200° C. The cooled mixture was filtered and the residue washed with EtOAc. The filtrate and washings were combined and evaporated under reduced pressure to leave a dark brown gum. The gum was purified by MDAP to give the title compound as a pale cream solid (44 mg, 42%).

LC/MS: m/z 467 [MH]⁺, RT 4.14 min.

Example 405 8-Chloro-1-[3-(3′-chloro-3-biphenylyl)propyl]-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A mixture of 1-[3-(3-bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.22 mmol) and 3-chlorophenyl boronic acid (35 mg, 0.22 mmol) was stirred in isopropanol (0.35 ml). A solution of sodium carbonate (70 mg, 0.66 mmol) in water (0.35 ml) was added to the mixture followed by 10% palladium on carbon (6 mg, Degussa type E101 NE/W). The mixture was heated in the microwave at 160° C. for 10 min, then filtered (glass fibre filter) and the residues washed with IPA. The filtrate and washings were combined and evaporated under reduced pressure to leave a gum. The gum was partitioned between DCM and water. The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organic phases were dried (MgSO₄) and concentrated to leave a foam. The foam was purified by MDAP to give the title compound as a colourless gum (40 mg, 37%).

LC/MS: m/z 485 [MH]⁺, RT 4.27 min.

The following compounds (Table 26) were prepared using a method analogous to that for 8-chloro-1-[3-(3′-chloro-3-biphenylyl)propyl]-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (Example 405) above, from the corresponding boronic acid, except that the 2-chlorophenyl analogue was heated in the microwave at 160° C. for 10 min twice while in the work up 1M hydrochloric acid was used instead of water. Also the EtOAc extraction was omitted.

TABLE 26 Yield Example Structure (mg) LC/MS: 406

51 m/z 451 [MH]⁺ RT 4.02 min 1-[3-(3-biphenylyl)propyl]-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6-dione 407

56 m/z 485 [MH]⁺ RT 4.15 min 8-chloro-1-[3-(2′-chloro-3-biphenylyl)propyl]- 3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Example 408 3-Butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione

3-Butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.31 mmol) and NCS (41 mg, 0.31 mmol) were suspended in MeCN (5 ml) and heated at 120° C. under microwave irradiation for 10 min. The reaction mixture was concentrated under reduced pressure and the title compound isolated using HPLC.

¹H NMR (CDCl₃) δ: 0.96 (3H, t), 1.37-1.43 (2H, m), 1.70-1.78 (2H, m), 2.00-2.09 (2H, m), 2.73 (2H, t), 4.08 (2H, t), 4.14 (2H, t), 7.13-7.26 (5H, m), 12.6 (1H, br.s).

LC/MS: m/z 361 [MH]⁺.

b) 3-Butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione

3-Butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione (0.6 g, 1.44 mmol) was dissolved in acetic acid (35 ml), 20% palladium hydroxide on carbon (0.366 g) was added, and the mixture was shaken under hydrogen (at 50 psi) overnight. The catalyst was removed by filtration through Celite® and washed with acetic acid. The filtrate was concentrated under reduced pressure and the title compound isolated using HPLC (0.385 g, 82%).

LC/MS: m/z 327 [MH]⁺.

c) 3-Butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione

7-Benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione (0.5 g, 1.68 mmol) and potassium carbonate (0.347 g, 2.5 mmol) were suspended in DMF (20 ml), (3-bromopropyl)benzene (390 mg, 1.96 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound.

¹H NMR (CDCl₃) δ: 0.95 (3H, t), 1.34-1.43 (2H, m), 1.68-1.76 (2H, m), 1.98-2.07 (2H, m), 2.71 (2H, t), 4.05-4.10 (4H, m), 5.49 (2H, s), 7.19-7.24 (5H, m), 7.33-7.38 (5H, m), 7.52 (1H, s).

LC/MS: m/z 417 [MH]⁺.

d) 7-Benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione

7-Benzyl-3,7-dihydro-1H-purine-2,6-dione (17.14 g, 70.8 mmol) [Synthetic Communications, 20(16), 2459-2467, 1990] and potassium carbonate (11.43 g, 82.8 mmol) were suspended in DMF (400 ml) at 40° C. After stirring for thirty minutes, butyl iodide (8.76 ml, 77.0 mmol) was added, and the mixture was stirred at 40° C. overnight. 50% Aqueous acetic acid (60 ml) was added, and the solution was concentrated under reduced pressure. The residue was suspended in water (500 ml), and the products were extracted into chloroform. The organics were collected, concentrated, and product was isolated using flash chromatography eluting with 1% methanol in dichloromethane (9.49 g, 45%).

¹H NMR (CDCl₃) δ: 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40 (5H, m), 7.56 (1H, s), 8.21 (1H, br.s).

LC/MS: m/z 299 [MH]⁺.

Example 409 3-Butyl-8-chloro-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure for 3-butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione, from 3-butyl-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione and NCS.

¹H NMR (CDCl₃) δ: 0.95 (3H, t), 1.36-1.45 (2H, m), 1.71-1.79 (2H, m), 4.11 (2H, t), 4.29 (2H, t), 4.54 (2H, t), 6.87-6.94 (3H, m), 7.21-7.27 (2H, m), 13.10 (1H, br.s).

LC/MS: m/z 363 [MH]⁺.

b) 3-Butyl-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure outlined for 3-butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione, from 3-butyl-7-(phenylmethyl)-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione.

LC/MS: m/z 329 [MH]⁺.

c) 3-Butyl-7-(phenylmethyl)-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure outlined for 3-butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione, from 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione and 2-bromoethyl phenyl ether.

¹H NMR (CDCl₃) δ: 0.95 (3H, t), 1.35-1.44 (2H, m), 1.69-1.78 (2H, m), 4.07-4.11 (2H, m), 4.26 (2H, t), 4.434 (2H, t), 5.49 (2H, s), 6.87-7.38 (10H, m), 7.55 (1H, s).

LC/MS: m/z 419 [MH]⁺.

Example 410 8-Chloro-3-methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure outlined for 3-butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione, from 3-methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione and NCS.

¹H NMR (CDCl₃) δ: 2.01-2.12 (2H, m), 2.74 (2H, t), 3.57 (3H, s), 4.14 (2H, t), 6.99-7.24 (5H, m), 12.5 (1H, br.s).

LC/MS: m/z 319 [MH]⁺.

b) 3-Methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure outlined for 3-butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione, from 3-methyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione.

LC/MS: m/z 285 [MH]⁺.

c) 3-Methyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure outlined for 3-butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione, from 3-methyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione and (3-bromopropyl)benzene.

LC/MS: m/z 375 [MH]⁺.

d) 3-Methyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared using the procedure described for 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione using methyl iodide (0.28 ml, 4.46 mmol). Purification was achieved by trituration. The product was isolated as a solid, insoluble in chloroform and water (0.334 g, 57%).

¹H NMR (DMSO-d₆) δ: 3.34 (3H, s), 5.44 (2H, s), 7.26-7.37 (5H, m), 8.21 (1H, s), 11.13 (1H, s).

LC/MS: m/z 257 [MH]⁺.

Example 411 8-Chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-5-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-5-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione

8-Chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (156 mg, 0.5 mmol) was dissolved in anhydrous THF (5 ml) under nitrogen and [1-(phenylmethyl)-1H-indol-5-yl]methanol (138 mg, 0.58 mmol) was added. After several minutes triphenylphosphine (168 mg, 0.63 mmol) was added followed 5-10 min later by DBAD (155 mg, 0.67 mmol) and the solution stirred for 18 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh₃)₄ (63 mg, 0.054 mmol) was added and the mixture degassed once more. Morpholine (0.461 ml, 5.3 mmol) was added and the mixture was stirred under nitrogen for 24 h. A further quantity of Pd(PPh₃)₄ (58 mg, 0.05 mmol) was added and the mixture was stirred under nitrogen for 96 h. The mixture was diluted with EtOAc and washed with 2M HCl (5 ml) then brine (15 ml), dried (MgSO₄) and concentrated. The crude material was purified by an aminopropyl SPE (eluent MeOH to wash through the impurities, then with 3-4% AcOH/MeOH). The product fractions were combined and concentrated to give the title compound as a white solid (43 mg, 17%).

LC/MS: m/z 476 [MH]⁺, RT 3.78 min.

b) [1-(Phenylmethyl)-1H-indol-5-yl]methanol

Methyl 1-(phenylmethyl)-1H-indole-5-carboxylate (1.17 g, 4.4 mmol) was dissolved in anhydrous THF under nitrogen and cooled to −5° C. 1M Lithium aluminumhydride in diethylether (4.0 ml) was added slowly. The cooling bath was removed and the reaction mixture was left overnight at room temperature. The reaction was quenched by the sequential addition of water (0.15 ml), 15% NaOH (0.15 ml) followed by water (0.45 ml) then ethyl acetate and sodium sulphate were added and the mixture stirred for 0.5 h. The insoluble material was filtered and washed well with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound as a cream solid which darkened on standing (1.04 g, 100%).

LC/MS: m/z 238 [MH]⁺, RT 3.03 min.

The following alcohols were prepared by reduction of the corresponding methyl ester in a similar manner:

[1-(Phenylmethyl)-1H-indol-4-yl]methanol

LC/MS: m/z 238 [MH]⁺, RT 3.03 min.

[2-(Phenylmethyl)-1,3-benzoxazol-4-yl]methanol

LC/MS: m/z 240 [MH]⁺, RT 2.02 min.

c) Methyl 1-(phenylmethyl)-1H-indole-5-carboxylate

Methyl 1H-indole-5-carboxylate (1.0 g, 5.7 mmol) was dissolved in anhydrous DMF under nitrogen and cooled to 2° C. Sodium hydride (0.25 g, 6.3 mmol, 60% in paraffin) was added. After 0.5 h benzyl bromide (0.75 ml, 6.0 mmol) was added and the reaction mixture stirred for 4 hr at room temperature, then left overnight. The reaction mixture was poured into water (50 ml) and ethyl acetate (10 ml). The aqueous phase was extracted further with ethyl acetate (50 ml). The combined organic phases were washed with dil. ammonia then brine, dried (MgSO₄) and concentrated in vacuo. The crude product was purified on a 50 g Si SPE (gradient elution cyclohexane/ethyl acetate 8% to 16%). The relevant fractions were concentrated in vacuo to give the title compound as a white solid (1.17 g, 77%)

LC/MS: m/z 266 [MH]⁺, RT 3.60 min.

Methyl 1-(phenylmethyl)-1H-indole-4-carboxylate was prepared in a similar manner

LC/MS: m/z 266 [MH]⁺, RT 3.58 min.

Methyl 2-(phenylmethyl)-1,3-benzoxazole-5-carboxylate

Trimethylbenzylorthoformate (1.34 g, 6.8 mmol) was dissolved in methanol (2 ml) and methyl-3-amino-hydroxybenzoate (0.56 g, 3.35 mmol) was added followed by conc. hydrochloric acid (9.1 ml). The mixture was stirred at reflux for 4.75 h, allowed to cool and evaporated in vacuo. The residue was partitioned between diethyl ether (10 ml) and 2M NaOH solution (5 ml). The organic phase was washed with water (5 ml) and the combined aqueous phases were back extracted with ether (10 ml). The combined organic phases were dried (MgSO₄) and concentrated in vacuo to leave an orange oil (1.37 g). The crude product was purified on silica (40 g SPE, gradient elution cyclohexane/ethyl acetate 0-100%) to give the title compound as a white solid (0.72 g, 80%).

LC/MS: m/z 268 [MH]⁺, RT 3.27 min.

3-[3-(Phenylmethyl)phenyl]-1-propanol

3-[3-(phenylcarbonyl)phenyl]propanoic acid (491 mg, 1.96 mmol) was dissolved in anhydrous THF under nitrogen and cooled to 0° C. 1M LiAlH₄ in ether (2.13 ml) was added slowly and the reaction mixture was stirred at room temperature for 20 h. The reaction was cooled in ice and tetrahydrofuran (5 ml) and 1M LiAlH₄ in ether solution (2.2 ml) added. The reaction mixture was heated at reflux for 7 hr then left at room temperature for 3 days. The reaction was quenched with sequentially, water (0.16 ml), 15% NaOH (0.16 ml) and water (0.47 ml) then diluted with ethyl acetate and dried with sodium sulphate. The insoluble material was filtered and thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo to give 3-{3-[hydroxy(phenyl)methyl]phenyl}-1-propanol as a white opaque oil (0.42 g, 90%)

LC/MS: m/z 243 [MH]⁺, RT 2.71 min.

The above material (200 mg, 0.82 mmol) was dissolved in anhydrous dichloromethane (5 ml) and triethylsilane (0.53 ml, 3.2 mmol) followed by trifluoroacetic acid (0.36 ml, 4.1 mmol) were added. The reaction mixture was stirred for 1 h then washed with saturated sodium hydrogen carbonate solution. The organic phase was filtered through a hydrophobic fit and concentrated in vacuo. The crude product was purified over silica (4 g SPE, gradient elution cyclohexane/ethyl acetate 0-30%) to give the title compound as a colourless oil (68 mg, 37%).

LC/MS: m/z 227 [MH]⁺, RT 3.25 min.

The following compounds (Table 27) were prepared using a method analogous to that for 8-chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-5-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione from the corresponding alcohols as described above.

TABLE 27 Yield Example Structure (mg) LC/MS: 412

49 m/z 476 [MH]⁺ RT 3.82 min 8-chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol- 4-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione 413

70 m/z 465 [MH]⁺ RT 4.01 min 8-chloro-3-pentyl-1-{3-[3- (phenylmethyl)phenyl]propyl}-3,7-dihydro-1H- purine-2,6-dione 414

174 m/z 478 [MH]⁺ RT 3.70 min 8-chloro-3-pentyl-1-{[2-(phenylmethyl)-1,3- benzoxazol-5-yl]methyl}-3,7-dihydro-1H-purine- 2,6-dione

Example 415 8-Chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.084 g, 0.18 mmol) and Pd(PPh₃)₄ (0.042 g, 0.035 mmol) in THF (5 ml) was degassed (sequential evacuation followed by addition of nitrogen×3) then morpholine (0.25 ml, 2.8 mmol) added and the mixture stirred overnight. The solution was loaded onto an aminopropyl SPE (5 g) and eluted with MeOH to remove by-products then with 5% AcOH/MeOH to isolate the title compound, after concentration, as an oil (0.022 g, 29%).

LC/MS: m/z 433 [MH]⁺

b) 8-Chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.107 g, 0.36 mmol) and 1-chloro-6-phenyl-2-hexanol (0.107 g, 0.5 mmol) in DMF (5 ml) was added cesium carbonate (0.24 g, 0.74 mmol) and the mixture heated at 60° C. for 3 h, whereupon a further 80 mg of cesium carbonate was added and heating continued at 100° C. for 18 h. The solution was allowed to cool, concentrated and the residues purified by chromatography over silica (20 g SPE, eluting with first with DCM then DCM/10% ether) to yield the title compound as a yellow oil (0.085 mg, 53%).

LC/MS: m/z 473 [MH]⁺

Example 416 8-Chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.35 g, 0.67 mmol), Pd(PPh₃)₄ (0.082 g, 0.07 mmol) and morpholine (0.6 ml, 6.7 mmol) in THF (10 ml) was degassed (sequential evacuation followed by addition of nitrogen×3) then stirred for 4 h. The solution was then loaded onto an aminopropyl SPE (5 g) and eluted first with MeOH then 5% AcOH/MeOH to provide the title compound containing a small impurity. Further purification over silica (10 g SPE, gradient elution ether/ethyl acetate 1:0 to 0:1) provided the title compound as a clear oil (0.10 g, 31%).

LC/MS: m/z 486 [MH]⁺

b) 8-Chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione

Prepared as with 8-chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using 1-(4-bromobutyl)-3-(phenylmethyl)-2-pyrrolidinone as the alkylating agent, potassium carbonate as base and heating at 50° C. for 18 h. Yield 86%.

LC/MS: m/z 526 [MH]⁺

c) 1-(4-bromobutyl)-3-(phenylmethyl)-2-pyrrolidinone

To a solution of 3-(phenylmethyl)-2-pyrrolidinone (0.23 g, 1.3 mmol) and 1,4-dibromobutane (0.57 g, 4.2 mmol) in DMF (5 ml) was added sodium t-butoxide (0.151 g, 1.6 mmol) and the solution stirred for 18 h. The solution was concentrated and the residues chromatographed over silica (20 g SPE, eluting first with cyclohexane then with DCM) to provide the title compound as a colourless oil containing a trace of DMF (0.25 g, 61%).

LC/MS: m/z 311 [MH]⁺ Example 417 8-Chloro-1-{4-[2-oxo-1-(phenylmethyl)-3-pyrrolidinyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-{4-[2-oxo-1-(phenylmethyl)-3-pyrrolidinyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.086 g, 0.29 mmol) and 3-(4-bromobutyl)-1-(phenylmethyl)-2-pyrrolidinone (0.17 g, 0.55 mmol, 1:1 mixture with 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one) in THF (5 ml) was added potassium carbonate (0.08 g, 0.58 mmol) and the mixture heated and stirred at 50° C. for 18 h. The solution was allowed to cool then degassed (sequential evacuation followed by addition of nitrogen×3) and Pd(PPh₃)₄ (0.09 g, 0.077 mmol) followed by morpholine (0.2 ml, 2.2 mmol) added and the solution stirred at ambient temperature for 18 h. The solution was separated between ethyl acetate and dil HCl and the organics washed with brine, dried and concentrated. Purification of the residues using an aminopropyl SPE (5 g) eluting first with MeOH then 5% AcOH/MeOH yielded the title compound as a yellow oil which crystallised on standing under ether (0.031 g, 22%).

LC/MS: m/z 486 [MH]⁺

b) 3-(4-Bromobutyl)-1-(phenylmethyl)-2-pyrrolidinone

To a solution of 1-(phenylmethyl)-2-pyrrolidinone (0.47 g, 2.7 mmol) in THF (10 ml) at −78° C. was added lithium hexamethyldisilylazine (2.8 ml, 2.7 mmol, 1M solution) over 5 min. After 15 min 1,4-dibromobutane (0.32 ml, 2.7 mmol) was added and the solution allowed to attain ambient temperature over 2 h then stirred for a further 18 h. The solution was separated between ethyl acetate and water and the organics isolated, dried and concentrated. Chromatography over silica (20 g SPE) eluting with cyclohexane then DCM and finally ether provided a clear oil which was a 1:1 mixture of the title compound and 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one (0.17 g). This was used in the next step without further purification.

LC/MS: m/z 310, 312 [MH]⁺

Example 418 8-Chloro-1-(5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}pentyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g, 0.61 mmol) in THF (5 ml) was added 5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}-1-pentanol (0.191 g, 0.61 mmol; prepared in similar fashion to Example 35), triphenylphosphine (0.36 g, 1.3 mmol) and finally dibenzylazodicarboxylate (0.40 g, 1.3 mmol). The solution was stirred for 18 h after which Pd(PPh₃)₄ (0.16 g, 0.137 mmol) followed by morpholine (0.75 ml, 8.3 mmol) was added and the solution stirred at ambient temperature for 6 h. The solution was loaded onto an aminopropyl SPE (5 g) and eluted with MeOH then 5% AcOH/MeOH to yield the title compound containing minor impurities. Further chromatography (silica SPE, 20 g) eluting with ether yielded the title compound as a white solid (0.061 g, 18%).

LC/MS: m/z 553 [MH]⁺ Example 419 8-Chloro-3-pentyl-1-{5-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]pentyl}-3,7-dihydro-1H-purine-2,6-dione

To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.093 g, 0.3 mmol) in THF (5 ml) was added 5-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-pentanol (0.077 g, 0.3 mmol; prepared in similar fashion to Example 87b), triphenylphosphine (0.17 g, 0.6 mmol) and finally dibenzylazodicarboxylate (0.20 g, 0.6 mmol). The solution was stirred for 18 h, degassed, after which Pd(PPh₃)₄ (0.08 g, 0.07 mmol) followed by morpholine (0.35 ml, 3.9 mmol) was added and the solution stirred at ambient temperature for 6 h. The solution was loaded onto an aminopropyl SPE (5 g) and eluted with MeOH then 5% AcOH/MeOH to yield the title compound as a cream solid (0.051 g. 34%).

LC/MS: m/z 485 [MH]⁺

Example 420 8-Chloro-1-{3-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]propyl}-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

Prepared as with 8-chloro-1-(5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}pentyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione using 3-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]-1-propanol. The final product material was washed with ether to yield the title compound as a cream solid (30%).

LC/MS: m/z 475 [MH]⁺ Example 421 3-Butyl-8-chloro-1-{4-[5-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of the 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (18 mg, 0.14 mmol) in DMF (0.5 ml) was treated with CDI (23 mg, 0.14 mmol) at rt for 1 h. A solution of (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.14 mmol) in DMSO (0.4 ml) was added to the mixture then heated to 100° C. for 18 h. The reaction mixture was purified by MDAP to give the title compound as a white solid (18 mg).

LC/MS: m/z 448 [MH]⁺, RT 2.86 min.

The following compounds (Table 28) were prepared using a method analogous to that for Example 421, using the appropriate carboxylic acid.

TABLE 28 Exam- Yield ple Structure Name (mg) LC/MS 422

3-butyl-8-chloro-1- {4-[5-(1H-imidazol-2- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 16 m/z 433 [MH]⁺ RT 2.79 min 423

3-butyl-8-chloro-1- (4-{5-[4- (trifluoromethyl)-1H- pyrazol-5-yl]-1,2,4- oxadiazol-3-yl}butyl)- 3,7-dihydro-1H- purine-2,6-dione 19 m/z 501 [MH]⁺ RT 3.28 min 424

3-butyl-8-chloro-1- {4-[5-(2-chloro-3- thienyl)-1,2,4- oxadiazol-3-yl]butyl)- 3,7-dihydro-1H- purine-2,6-dione 26 m/z 483 [MH]⁺ RT 3.59 min 425

3-butyl-8-chloro-1- {4-[5-(3-methyl-5- isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 25 m/z 448 [MH]⁺ RT 3.21 min 426

3-butyl-8-chloro-1- {4-[5-(1-methyl-1H- imidazol-4-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 16 m/z 447 [MH]⁺ RT 2.74 min 427

3-butyl-8-chloro-1- {4-(5-(1-methyl-1H- imidazol-2-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 9 m/z 447 [MH]⁺ RT 2.91 min 428

3-butyl-8-chloro-1- {4-[5-(1H-1,2,4- triazol-3-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 10 m/z 434 [MH]⁺ RT 2.73 min 429

3-butyl-8-chloro-1- {4-[5-(5-isothiazolyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 17 m/z 450 [MH]⁺ RT 3.34 min 430

3-butyl-8-chloro-1- {4-[5-(2-furanyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 26 m/z 433 [MH]⁺ RT 3.27 min 431

3-butyl-8-chloro-1- {4-[5-(5-methyl-2- thienyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 29 m/z 463 [MH]⁺ RT 3.61 min 432

3-butyl-8-chloro-1- {4-[5-(3-chloro-4- methyl-2-thienyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 30 m/z 497 [MH]⁺ RT 3.76 min 433

3-butyl-8-chloro-1- {4-[5-(4-methyl-1,3- oxazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 25 m/z 448 [MH]⁺ RT 3.13 min 434

3-butyl-8-chloro-1- {4-[5-(3-isoxazolyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 23 m/z 434 [MH]⁺ RT 3.20 min 435

1-{4-[5-(5-acetyl-2- thienyl)-1,2,4- oxadiazol-3-yl]butyl}- 3-butyl-8-chloro-3,7- dihydro-1H-purine- 2,6-dione 28 m/z 491 [MH]⁺ RT 3.43 min 436

3-butyl-8-chloro-1- {4-[5-(5-chloro-2- furanyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 467 [MH]⁺ RT 3.51 min 437

3-butyl-8-chloro-1- (4-{5-[5- (trifluoromethyl)-2- furanyl]-1,2,4- oxadiazol-3-yl}butyl)- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 501 [MH]⁺ RT 3.61 min 438

3-butyl-8-chloro-1- {4-[5-(3-methyl-2- furanyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 447 [MH]⁺ RT 3.43 min 439

3-butyl-8-chloro-1- {4-[5-(1-methyl-1H- pyrazol-3-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 25 m/z 447 [MH]⁺ RT 3.02 min 440

3-butyl-8-chloro-1- {4-[5-(1-methyl-1H- pyrazol-4-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 8 m/z 447 [MH]⁺ RT 2.99 min 441

3-butyl-8-chloro-1- {4-[5-(3-thienyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 19 m/z 449 [MH]⁺ RT 3.43 min 442

3-butyl-8-chloro-1- {4-[5-(5-methyl-1H- pyrazol-3-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 26 m/z 447 [MH]⁺ RT 3.03 min 443

3-butyl-8-chloro-1- {4-[5-(3-methyl-2- thienyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 463 [MH]⁺ RT 3.62 min 444

3-butyl-8-chloro-1- {4-[5-(1H-pyrrol-2- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 13 m/z 432 [MH]⁺ RT 3.26 min 445

3-butyl-8-chloro-1- {4-[5-(2-methyl-3- thienyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 18 m/z 463 [MH]⁺ RT 3.64 min 446

3-butyl-8-chloro-1- {4-[5-(4-methyl-1,3- thiazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 24 m/z 464 [MH]⁺ RT 3.26 min 447

3-butyl-8-chloro-1- {4-[5-(1H-pyrazol-3- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 20 m/z 433 [MH]⁺ RT 3.00 min 448

3-butyl-8-chloro-1- {4-[5-(3-ethyl-5- isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 20 m/z 462 [MH]⁺ RT 3.43 min 449

3-butyl-8-chloro-1- {4-[5-(5-ethyl-3- isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 23 m/z 462 [MH]⁺ RT 3.46 min 450

3-butyl-8-chloro-1- {4-[5-(1,3-thiazol-5- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 20 m/z 450 [MH]⁺ RT 3.13 min 451

3-butyl-8-chloro-1- {4-[5-(1H-indazol-3- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 24 m/z 483 [MH]⁺ RT 3.50 min 452

1-{4-[5-(1- benzofuran-2-yl)- 1,2,4-oxadiazol-3- yl]butyl}-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6-dione 6 m/z 483 [MH]⁺ RT 3.72 min 453

3-butyl-8-chloro-1- {4-[5-(5-methyl-3- isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 13 m/z 448 [MH]⁺ RT 3.30 min 454

3-butyl-8-chloro-1- {4-[5-(2-methyl-1,3- thiazol-4-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 20 m/z 464 [MH]⁺ RT 3.14 min 455

3-butyl-8-chloro-1- {4-[5-(4-methyl- 1,2,3-thiadiazol-5- yl)-1,2,4-oxadiazol- 3-yl]butyl)-3,7- dihydro-1H-purine- 2,6-dione 14 m/z 465 [MH]⁺ RT 3.40 min 456

3-butyl-8-chloro-1- {4-[5-(3-methyl-2- thioxo-2,3-dihydro- 1H-imidazol-4-yl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 16 m/z 479 [MH]⁺ RT 3.08 min 457

3-butyl-8-chloro-1- {5-[5-(1,2,5- thiadiazol-3-yl)- 1,2,4-oxadiazol-3- yl]butyl)-3,7-dihydro- 1H-purine-2,6-dione 24 m/z 451 [MH]⁺ RT 3.27 min 458

3-butyl-8-chloro-1- {4-[5-(3-furanyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 21 m/z 433 [MH]⁺ RT 3.29 min 459

3-butyl-8-chloro-1- {4-[5-(1-methyl-1H- pyrazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 23 m/z 447 [MH]⁺ RT 3.22 min 460

3-butyl-8-chloro-1- {4-[5-(1,3-thiazol-4- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 20 m/z 450 [MH]⁺ RT 3.06 min 461

N-(4-{3-[4-(3-butyl-8- chloro-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1-yl)butyl]- 1,2,4-oxadiazol-5- yl}-3- chlorophenyl)acetamide 23 m/z 534 [MH]⁺ RT 3.44 min 462

N-(4-{3-(4-(3-butyl-8- chloro-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1-yl)butyl]- 1,2,4-oxadiazol-5- yl}phenyl)acetamide 16 m/z 500 [MH]⁺ RT 3.23 min 463

3-butyl-8-chloro-1- {4-[5-(2-thienyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 27 m/z 449 [MH]⁺ RT 3.45 min 464

3-butyl-8-chloro-1- {4-[5-(1-methyl-1H- pyrrol-2-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 15 m/z 446 [MH]⁺ RT 3.45 min

Example 465 1-{4-[1,3-Benzoxazol-2-yl(methyl)amino]butyl}-8-chloro-3-ethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 2-chloro-1,3-benzoxazole (0.46 g, 3 mmol) in THF (20 ml) was treated with 1-methylpyrrolidine (0.26 g, 3 mmol) and the reaction mixture heated at reflux for 6 h, then cooled and evaporated to dryness. Purification by flash chromatography [Isco Companion, 12 g Redisep cartridge, gradient elution from cyclohexane to cyclohexane/diethyl ether (3:2)] revealed 0.52 g (73% yield) of N-(4-chlorobutyl)-N-methyl-1,3-benzoxazol-2-amine as a colourless oil. LC/MS: m/z 239 [MH]⁺, RT 3.12 min.

A solution of 8-chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.112 g, 0.44 mmol) in DMF (10 ml) was treated with potassium carbonate (0.08 g, 0.6 mmol) and N-(4-chlorobutyl)-N-methyl-1,3-benzoxazol-2-amine (0.12 g, 0.5 mmol). The reaction mixture was heated at 75° C. for 18 h and then cooled to ambient temperature. The mixture was degassed by the repeated application of vacuum followed by backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) and morpholine (0.5 ml, 5.7 mmol). Stirred for 4 h under a nitrogen atmosphere at ambient temperature after which time the mixture was evaporated to dryness and the residue partitioned between chloroform (40 ml) and saturated aqueous ammonium chloride (40 ml). The organic phase was evaporated to dryness and the residue dissolved in methanol (5 ml) and added to a 5 g aminopropyl SPE cartridge which was subsequently washed with methanol and the product eluted with a 5% solution of acetic acid in methanol. Combined product-containing fractions were evaporated to dryness and the product purified by MDAP to give the title compound as a white solid (0.043 g, 23%).

LC/MS: m/z 417 [MH]⁺, RT 2.91 min.

The following compounds (Table 29) were prepared by a method analogous to that for Example 465.

TABLE 29 Yield Example Structure Precursor (mg) LC/MS 466

8-chloro-7-(2- propen-1-yl)-3- propyl-3,7-dihydro- 1H-purine-2,6- dione 47 m/z 431 [MH]⁺ RT 3.09 min 1-{4-[1,3-benzoxazol-2- yl(methyl)amino]butyl}-8- chloro-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 467

3-butyl-8-chloro-7- (2-propen-1-yl)- 3,7-dihydro-1H- purine-2,6-dione 61 m/z 445 [MH]⁺ RT 3.28 min 1-{4-[1,3-benzoxazol-2- yl(methyl)amino]butyl}-3- butyl-8-chloro-3,7-dihydro- 1H-purine-2,6-dione

Example 468 3-Butyl-8-chloro-1-[5-(1,3-dioxo-1,3-dihydro-2H-Isoindol-2-yl) pentyl]-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.5 g, 1.8 mmol) in DMF (20 ml) was treated with potassium carbonate (0.3 g, 2.1 mmol) and 1,5-dibromopentane (1.2 ml, 8.9 mmol) and then heated at 50° C. for 2 h. The mixture was cooled and evaporated to dryness. The residue was partitioned between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was extracted with a further ethyl acetate (30 ml) and the combined organics dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography [Isco Companion, 40 g Redisep cartridge, gradient elution from cyclohexane to cyclohexane/ethyl acetate (1:1)] to reveal 0.663 g (87%) of 1-(5-bromopentyl)-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione as a colourless oil. LC/MS: m/z 431/433 [MH]⁺, RT 3.76 min.

To a solution of 1-(5-bromopentyl)-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.642 g, 1.5 mmol) in DMF (10 ml) was added potassium phthalimide (0.303 g, 1.6 mmol) and the mixture heated at 50° C. for 2 h then cooled. The mixture was degassed by the repeated application of vacuum followed by backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.15 mmol) and morpholine (1.3 ml, 15 mmol). The mixture was allowed to stand at ambient temperature under a blanket of nitrogen for 18 h after which time the mixture was evaporated and the residue partitioned between chloroform (30 ml) and saturated aqueous ammonium chloride (30 ml). The aqueous phase was extracted with a further chloroform (30 ml) and the combined organics dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in methanol (5 ml) and added to a 10 g aminopropyl SPE cartridge which was subsequently washed with methanol and the product eluted with a 5% solution of acetic acid in methanol. Product-containing fractions were evaporated and then purification by MDAP to give N-[5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentyl]-2-(4-morpholinylcarbonyl)benzamide as a white solid (0.137 g, LC/MS: m/z 545 [MH]⁺, RT 2.77 min) and the title compound as a white solid (0.239 g, 35%).

LC/MS: m/z 458 [MH]⁺, RT 3.33 min.

Example 469 8-Chloro-1-{4-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]butyl}-3-ethyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-1-{4-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]butyl}-3-ethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDI (0.029 g, 0.18 mmol) and the mixture stirred at room temperature for 1 h. Subsequently, the mixture was treated with 2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to 120° C. for 30 min. The product was purified from the crude mixture using MDAP. Product-containing fractions were evaporated using a stream of nitrogen and the resulting colourless gum triturated in ether and dried to reveal the title compound as a white solid (50 mg, 70%).

LC/MS: m/z 451 [MH]⁺, RT 2.23 min.

b) 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid

A solution of ethyl 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (2.3 g, 6.7 mmol) in methanol (75 ml) was treated with water (3 ml) and lithium hydroxide (0.481 g, 20.1 mmol) and the mixture stirred at 40° C. for 17 h. The mixture was evaporated to dryness and the residue treated with 50 ml of ethyl acetate and 50 ml of water. The 2 phases were separated and the aqueous phase adjusted to pH5 using 2M aqueous hydrochloric acid. The precipitated product was filtered off and dried to yield 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid as a white solid (1.99 g, 95%).

LC/MS: m/z 315 [MH]⁺, RT 2.34 min.

c) Ethyl 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate

A solution of 8-chloro-7-(2-propen-1-yl)-3-ethyl-3,7-dihydro-1H-purine-2,6-dione (3 g, 11.8 mmol) in DMF (40 ml) was treated with potassium carbonate (1.9 g, 14.1 mmol) and ethyl 5-bromopentanoate (2.24 ml, 14.1 mmol) and the mixture heated in a nitrogen atmosphere at 70° C. for 5 h and then cooled. The mixture was degassed by the repeated application of vacuum followed by backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (1.36 g, 1.1 mmol) and morpholine (10.3 ml, 118 mmol). The mixture was stirred in a nitrogen atmosphere for 4 h and then evaporated to dryness. The residue was partitioned between 100 ml of ethyl acetate and 100 ml of water. The aqueous phase was re-extracted with 100 ml of ethyl acetate and the combined organics dried over magnesium sulfate, filtered and evaporated. The residue was triturated in diethyl ether, filtered and dried to reveal ethyl 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate compound as a white solid (2.3 g, 57%).

LC/MS: m/z 343 [MH]⁺, RT 2.73 min.

The following compounds (Table 30) were prepared by a method analogous to that for Example 469.

TABLE 30 Yield Example Structure Precursor (mg) LC/MS 470

5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 33 m/z 449 [MH]⁺ RT 3.27 min 8-chloro-1-{4-[3-(2- chlorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3-ethyl- 3,7-dihydro-1H-purine-2,6- dione 471

5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 32 m/z 415 [MH]⁺ RT 3.22 min 8-chloro-1-[4-(3-phenyl- 1,2,4-oxadiazol-5-yl)butyl]-3- ethyl-3,7-dihydro-1H-purine- 2,6-dione 472

5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 31 m/z 433 [MH]⁺ RT 3.26 min 8-chloro-3-ethyl-1-{4-[3-(4- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione 473

5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 2 m/z 417 [MH]⁺ RT 2.54 min 8-chloro-3-ethyl-1-{4-[3-(2- pyrazinyl)-1,2,4-oxadiazol-5- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione 474

5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 38 [MH]⁺ RT 3.12 min 8-chloro-3-ethyl-1-{4-[3-(2- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione 475

5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 29 m/z 447 [MH]⁺ RT 3.28 min 8-chloro-1-{4-[3-(2- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione 476

5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 11 m/z 429 [MH]⁺ RT 3.35 min 8-chloro-1-[4-(3-phenyl- 1,2,4-oxadiazol-5-yl)butyl]-3- propyl-3,7-dihydro-1H- purine-2,6-dione 477

5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 32 m/z 465 [MH]⁺ RT 3.40 min 8-chloro-1-{4-[3-(2,4- difluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione 478

5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 25 m/z 463 [MH]⁺ RT 3.40 min 8-chloro-1-{4-[3-(2- chlorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione 479

5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 26 m/z 447 [MH]⁺ RT 3.44 min 8-chloro-1-{4-[3-(4- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione 480

5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 25 m/z 431 [MH]⁺ RT 3.09 min 8-chloro-3-propyl-1-{4-[3-(2- pyrazinyl)-1,2,4-oxadiazol-5- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione

The following compounds (Table 31) were prepared using a method analogous to that for Example 158, using the appropriate acid.

TABLE 31 Yield Example Structure Name (mg) LC/MS 481

8-chloro-3-pentyl-1-{4- [5-(4-pyridinyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 8.0 m/z 458 [MH]⁺ RT 3.25 min 482

8-chloro-1-{4-[5-(3- fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 9.1 m/z 475 [MH]⁺ RT 3.73 min 483

8-chloro-1-{4-[5-(4- fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 16.1 m/z 475 [MH]⁺ RT 3.69 min 484

8-chloro-1-{4-[5-(2- methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 22.9 m/z 471 [MH]⁺ RT 3.82 min 485

8-chloro-1-{4-[5-(3- methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 18.0 m/z 471 [MH]⁺ RT 3.81 min 486

8-chloro-1-{4-[5-(4- methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 25.0 m/z 471 [MH]⁺ RT 3.80 min 487

8-chloro-1-{4-[5-(4- chlorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 16.6 m/z 491 [MH]⁺ RT 3.89 min 488

8-chloro-1-{4-[5-(3- chlorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 12.8 m/z 491 [MH]⁺ RT 3.91 min 489

8-chloro-1-(4-{5-[3- (methyloxy)phenyl]- 1,2,4-oxadiazol-3- yl}butyl)-3-pentyl-3,7- dihydro-1H-purine-2,6- dione 23.0 m/z 487 [MH]⁺ RT 3.71 min 490

8-chloro-1-(4-{5-[4- (methyloxy)phenyl]- 1,2,4-oxadiazol-3- yl}butyl)-3-pentyl-3,7- dihydro-1H-purine-2,6- dione 15.8 m/z 487 [MH]⁺ RT 3.67 min 491

8-chloro-1-[4-(5- cyclohexyl-1,2,4- oxadiazol-3-yl)butyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 16.1 m/z 468 [MH]⁺ RT 3.73 min 492

8-chloro-1-[4-(5- cyclopentyl-1,2,4- oxadiazol-3-yl)butyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione 11.7 m/z 449 [MH]⁺ RT 3.59 min 493

8-chloro-1-{4-[5-(1,1- dimethylethyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2.6-dione 19.8 m/z 437 [MH]⁺ RT 3.52 min 494

8-chloro-3-pentyl-1-{4- [5-(phenylmethyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 21.0 m/z 471 [MH]⁺ RT 3.55 min 495

8-chloro-3-pentyl-1-(4- {5-[(2,4,6- trifluorophenyl)methyl]- 1,2,4-oxadiazol-3- yl}butyl)-3,7-dihydro- 1H-purine-2.6-dione 29.3 m/z 525 [MH]⁺ RT 3.62 min 496

8-chloro-3-pentyl-1-{4- [5-(2-phenylethyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 18.4 m/z 485 [MH]⁺ RT 3.64 min 497

8-chloro-3-pentyl-1-{4- [5-(3-pyridinyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 8.2 m/z 458 [MH]⁺ RT 3.23 min

The following compounds (Table 32) were prepared using a method analogous to that for Example 36, using the appropriate tetrazole and 3-[3-alkyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate. MDAP was employed to further purify those compounds insufficiently pure following normal phase chromatography.

TABLE 32 Yield Example Structure Name (mg) LC/MS 498

3-butyl-8-chloro-1- (3-{5-[(4- methylphenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 35.1 m/z 457 [MH]⁺ RT 3.40 min 499

3-butyl-8-chloro-1- [3-(5-{(4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 43.6 m/z 511 [MH]⁺ RT 3.52 min 500

3-butyl-8-chloro-1- [3-(5-{[4- (methyloxy)phenyl] methyl}-2H-tetrazol- 2-yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 38.2 m/z 473 [MH]⁺ RT 3.24 min 501

3-butyl-8-chloro-1- (3-{5-[(2- fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 13.7 m/z 461 [MH]⁺ RT 3.07 min 502

3-butyl-8-chloro-1- (3-{5-[(3- fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 15.0 m/z 461 [MH]⁺ RT 3.10 min 503

3-butyl-8-chloro-1- (3-{5-[(4- fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 17.7 m/z 461 [MH]⁺ RT 3.10 min 504

3-butyl-8-chloro-1- (3-{5-[(2- chlorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 8.4 m/z 477 [MH]⁺ RT 3.17 min 505

3-butyl-8-chloro-1- (3-{5-[(3- chlorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 16.4 m/z 477 [MH]⁺ RT 3.23 min 506

3-butyl-8-chloro-1- (3-{5-[(4- chlorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 17.0 m/z 477 [MH]⁺ RT 3.24 min 507

3-butyl-8-chloro-1- (3-{5-[(2- methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 15.1 m/z 457 [MH]⁺ RT 3.15 min 508

3-butyl-8-chloro-1- (3-{5-[(3- methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 18.6 m/z 457 [MH]⁺ RT 3.18 min 509

3-butyl-8-chloro-1- (3-{5-[(4- methylphenyl)methyl]- 1H-tetrazol-1 yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 16.3 m/z 457 [MH]⁺ RT 3.19 min 510

3-butyl-8-chloro-1- [3-(5-{[3- (trifluoromethyl) phenyl]methyl}-1H- tetrazol-1- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 17.7 m/z 511 [MH]⁺ RT 3.31 min 511

3-butyl-8-chloro-1- [3-(5-{[4- (trifluoromethyl) phenyl]methyl}-1H- tetrazol-1- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 21.6 m/z 511 [MH]⁺ RT 3.33 min 512

3-butyl-8-chloro-1- [3-(5-{[2- (methyloxy)phenyl] methyl}-1H-tetrazol- 1-yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 16.3 m/z 473 [MH]⁺ RT 3.10 min 513

3-butyl-8-chloro-1- [3-(5-{[4- (methyloxy)phenyl] methyl}-1H-tetrazol- 1-yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 20.8 m/z 473 [MH]⁺ RT 3.05 min 514

3-butyl-8-chloro-1- {3-[5-(1- phenylcyclopropyl)- 1H-tetrazol-1- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 14.1 m/z 468 [MH]⁺ RT 3.16 min 515

3-butyl-8-chloro-1- {3-[5-(2- phenylethyl)-1H- tetrazol-1- yl]propyl)-3,7- dihydro-1H-purine- 2,6-dione 21.0 m/z 457 [MH]⁺ RT 3.15 min 516

3-butyl-8-chloro-1- {3-[5-(2- thienylmethyl)-1H- tetrazol-1- yl]propyl)-3,7- dihydro-1H-purine- 2,6-dione 11.8 m/z 448 [MH]⁺ RT 3.02 min 517

3-butyl-8-chloro-1- (3-{5-[(2,6- dichlorophenyl) methyl]-1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 12.4 m/z 512 [MH]⁺ RT 3.27 min 518

8-chloro-3-propyl-1- [3-(5-{[4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]3,7- dihydro-1H-purine- 2,6-dione 15.5 m/z 497 [MH]⁺ RT 3.38 min 519

8-chloro-1-(3-{5-[(2- chlorophenyl)methyl]-1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 1.6 m/z 463 [MH]⁺ RT 3.00 min 520

8-chloro-1-(3-{5-[(3- chlorophenyl)methyl]-1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 7.1 m/z 463 [MH]⁺ RT 3.06 min 521

8-chlorol-(3-{5-[(2- methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 7.2 m/z 443 [MH]⁺ RT 2.97 min 522

8-chloro-1-(3-{5-[(3- methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 5.7 m/z 443 [MH]⁺ RT 3.01 min 523

8-chloro-1-(3-{5-[(4- methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 5.5 m/z 443 [MH]⁺ RT 3.01 min 524

8-chloro-3-propyl-1- [3-(5-{[3- (trifluoromethyl) phenyl]methyl}-1H- tetrazol-1- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 3.3 m/z 497 [MH]⁺ RT 3.16 min 525

8-chloro-1-(3-{5-[(2- methylphenyl)methyl}- 2H-tetrazol-2- propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 24.1 m/z 443 [MH]⁺ RT 3.20 min 526

8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 1.3 m/z 447 [MH]⁺ RT 2.89 min 527

8-chloro-3-propyl-1- {3-[5-(2- thienylmethyl)-1H- tetrazol-1- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 5.2 m/z 435 [MH]⁺ RT 2.83 min 528

8-chloro-1-[3-(5-{[4- (methyloxy)phenyl] methyl}-1H-tetrazol- 1-yl)propyl]-3- propyl-3,7-dihydro- 1H-purine-2,6- dione 1.2 m/z 459 [MH]⁺ RT 2.87 min 529

8-chloro-1-[3-(5-{[4- (methyloxy)phenyl] methyl}-2H-tetrazol- 2-yl)propyl]-3- propyl-3,7-dihydro- 1H-purine-2,6- dione 19.7 m/z 459 [MH]⁺ RT 3.07 min 530

8-chloro-1-[3-(5-{[2- (methyloxy)phenyl] methyl}-1H-tetrazol- 1-yl)propyl]-3- propyl-3,7-dihydro- 1H-purine-2,6- dione 1.9 m/z 459 [MH]⁺ RT 2.92 min 531

3-butyl-8-chloro-1- {2-[5-(2- phenylethyl)-2H- tetrazol-2-yl]ethyl}- 3,7-dihydro-1H- purine-2,6-dione 44.0 m/z 443 [MH]⁺ RT 3.31 min 532

3-butyl-8-chloro-1- {2-[5-(2- phenylethyl)-1H- tetrazol-1-yl]ethyl}- 3,7-dihydro-1H- purine-2,6-dione 10.4 m/z 443 [MH]⁺ RT 3.12 min 533

3-butyl-8-chloro-1- [3-(5-{[2-fluoro-4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 24.5 m/z 529 [MH]⁺ RT 3.22 min 534

3-butyl-8-chloro-1- [3-(5-{(5-fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 25.3 m/z 529 [MH]⁺ RT 3.51 min 535

3-butyl-8-chloro-1- [3-(5-{[3-fluoro-4- (trifluoromethyl) phenyl]methyl)-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 11.5 m/z 529 [MH]⁺ RT 3.56 min 536

3-butyl-8-chloro-1- (3-{5-[(3,4,5- trifluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 19.4 m/z 497 [MH]⁺ RT 3.45 min 537

3-butyl-8-chloro-1- {3-[5-({3- [(trifluoromethyl)oxy] phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 27.2 m/z 527 [MH]⁺ RT 3.55 min 538

3-butyl-8-chloro-1- [3-(5-{(3-fluoro-5- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 19.8 m/z 529 [MH]⁺ RT 3.56 min 539

1-[3-(5-{[2,4- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6- dione 36.6 m/z 579 [MH]⁺ RT 3.72 min 540

1-[3-(5-{[2,5- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6- dione 50.3 m/z 579 [MH]⁺ RT 3.65 min 541

8-chloro-1-[3-(5-{[4- fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(4,4,4- trifluorobutyl)-3,7- dihydro-1H-purine- 2,6-dione 25.0 m/z 583 [MH]⁺ Rt 3.50 min 542

8-chloro-1-[3-(5-{(4- fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-[2- (methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 23.0 m/z 531 [MH]⁺ RT 3.16 min 543

8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[4-fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 13.1 m/z 545 [MH]⁺ RT 3.30 min 544

8-chloro-1-[3-(5-{[4- fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propy]-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 36.3 m/z 569 [MH]⁺ RT 3.46 min 545

8-chloro-1-[3-(5-{[4- fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 32.0 m/z 515 [MH]⁺ RT 3.37 min 546

3-butyl-8-chloro-1- [3-(5-{[4-fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 30.3 m/z 529 [MH]⁺ RT 3.53 min 547

1-[3-(5-{[3,5- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-8-chloro- 3-propyl-3,7- dihydro-1H-purine- 2,6-dione 22.9 m/z 565 [MH]⁺ RT 3.54 min 548

8-chloro-3-propyl-1- {3-[5-({4- [(trifluoromethyl)oxy]- phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 21.6 m/z 513 [MH]⁺ RT 3.42 min 549

8-chloro-1-(3-{5-[(2- chloro-6- fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 12.4 m/z 481 [MH]⁺ RT 3.20 min 550

8-chloro-3-propyl-1- [3-(5-{[2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 17.7 m/z 497 [MH]⁺ RT 3.26 min 551

8-chloro-1-(3-{5- [(3,5- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 21.6 m/z 465 [MH]⁺ RT 3.16 min 552

8-chloro-3-propyl-1- {3-[5-({2- [(trifluoromethyl)oxy] phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 22.3 m/z 513 [MH]⁺ RT 3.27 min 553

8-chloro-1-[3-(5-{[2- fluoro-4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 9.7 m/z 515 [MH]⁺ RT 3.40 min 554

8-chloro-1-[3-(5-{[5- fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 26.8 m/z 515 [MH]⁺ RT 3.26 min 555

8-chloro-1-[3-(5-{[3- fluoro-4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 20.7 m/z 515 [MH]⁺ RT 3.31 min 556

8-chloro-3-propyl-1- (3-{5-[(3,4,5- trifluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 10.2 m/z 483 [MH]⁺ RT 3.23 min 557

8-chloro-3-propyl-1- {3-[5-({3- [(trifluoromethyl)oxy] phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 9.8 m/z 513 [MH]⁺ RT 3.35 min 558

8-chloro-1-(3-{5- [(2,4- dichlorophenyl) methyl]-2H-tetrazol-2- yl}propy)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 27.6 m/z 497 [MH]⁺ RT 3.40 min 559

8-chloro-1-[3-(5-{[3- fluoro-5- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 17.6 m/z 515 [MH]⁺ RT 3.23 min 560

1-[3-(5-{[2,4- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-8-chloro- 3-propyl-3,7- dihydro-1H-purine- 2,6-dione 21.0 m/z 565 [MH]⁺ RT 3.40 min 561

1-[3-(5-{[2,5- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-8-chloro- 3-propyl-3,7- dihydro-1H-purine- 2,6-dione 9.7 mz 565 [MH]⁺ RT 3.50 min 562

1-[3-(5-{[3,5- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6- dione 28.1 m/z 579 [MH]⁺ RT 3.68 min 563

3-butyl-8-chloro-1- {3-[5-({4- [(trifluoromethyl)oxy] phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 32.1 m/z 527 [MH]⁺ RT 3.57 min 564

8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-[2- (methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 15.0 m/z 463 [MH]⁺ RT 2.89 min 565

8-chloro-3-[2- (ethyloxy)ethyl]-1- (3-{5-[(4- fluorophenyl)methyl]- 2H-tetrazol-2- yl)propyl)-3,7- dihydro-1H-purine- 2,6-dione 12.6 m/z 477 [MH]⁺ RT 3.03 min 566

8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 17.8 m/z 501 [MH]⁺ RT 3.21 min 567

8-chloro-3-[2- (methyloxy)ethyl]-1- [3-(5-{[2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 14.2 m/z 513 [MH]⁺ RT 3.10 min 568

8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 20.8 m/z 527 [MH]⁺ RT 3.18 min 569

8-chloro-1-[3-(5-{[2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 35.8 m/z 551 [MH]⁺ RT 3.35 min 570

8-chloro-3-[2- (methyloxy)ethyl]-1- [3-(5-{[3- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 15.3 m/z 513 [MH]⁺ RT 3.14 min 571

8-chloro-1-[3-(5-{[3- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 29.4 m/z 551 [MH]⁺ RT 3.42 min 572

8-chloro-1-(3-{5- [(2,4- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(2- (methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 17.8 m/z 481 [MH]⁺ RT 2.96 min 573

8-chloro-1-(3-{5- [(2,4- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7- dihydro-1H-purine- 2,6-dione 14.4 m/z 495 [MH]⁺ RT 2.86 min 574

8-chloro-1-(3-{5- [(2,4- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 29.9 m/z 518 [MH]⁺ RT 3.19 min 575

8-chloro-3-(2- (methyloxy)ethyl]-1- (3-{5-[(2,4,6- trifluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 21.3 m/z 499 [MH]⁺ RT 2.93 min 576

8-chloro-3-[2- (ethyloxy)ethyl]-1- (3-{5-[(2,4,6- trifluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 15.5 m/z 513 [MH]⁺ RT 2.93 min 577

8-chloro-1-(3-{5- [(2,4,6- trifluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 32.3 m/z 537 [MH]⁺ RT 3.29 min 578

8-chloro-1-(3-{5- [(3,4- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 14.5 m/z 481 [MH]⁺ RT 2.97 min 579

8-chloro-1-(3-{5- [(3,4- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7- dihydro-1H-purine- 2,6-dione 7.2 m/z 495 [MH]⁺ RT 3.06 min 580

8-chloro-1-(3-{5- [(3,4- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 27.8 m/z 519 [MH]⁺ RT 3.27 min 581

8-chloro-1-(3-{5- [(2,5- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 17.1 m/z 481 [MH]⁺ RT 2.89 min 582

8-chloro-1-(3-{5- [(2,5- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7- dihydro-1H-purine- 2,6-dione 13.5 m/z 495 [MH]⁺ RT 3.05 min 583

8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[3- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine 2,6-dione 14.6 m/z 527 [MH]⁺ RT 3.26 min 584

8-chloro-3-(4,4,4- trifluorobutyl)-1-[3- (5{[4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 12.1 m/z 565 [MH]⁺ RT 3.51 min 585

8-chloro-3-[2- (methyloxy)ethyl]-1- [3-(5-{[4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 17.3 m/z 513 [MH]⁺ RT 3.17 min 586

8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 15.2 m/z 527 [MH]⁺ RT 3.30 min 587

8-chloro-3-(4,4,4- trifluorobutyl)-1-[3- (5-{[2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 5.8 m/z 565 [MH]⁺ RT 3.46 min 588

8-chloro-1-(3-{5- [(2,5- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(4,4,4- trifluorobutyl)-3,7- dihydro-1H-purine- 2,6-dione 14.7 m/z 533 [MH]⁺ RT 3.34 min 589

8-chloro-1-[3-(5-{[4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 26.1 m/z 551 [MH]⁺ RT 3.46 min 590

8-chloro-1-(3-{5- [(2,5- difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 18.0 m/z 519 [MH]⁺ RT 3.29 min 591

8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]- 2H-tetrazo-2- yl}propyl)-3-[2- (methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 3.4 m/z 463 [MH]⁺ RT 2.84 min 592

8-chloro-3-[2- (ethyloxy)ethyl]-1- (3-{5-[(2- fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 8.2 m/z 477 [MH]⁺ RT 2.85 min 593

8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 32.7 m/z 501 [MH]⁺ RT 3.25 min 594

8-chloro-3-[2- (methyloxy)ethyl]-1- {3-[5-(1- phenylcyclopropyl)- 2H-tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 10.2 m/z 471 [MH]⁺ RT 2.93 min 595

8-chloro-3-[2- (ethyloxy)ethyl]-1- {3-[5-(1- phenylcyclopropyl)- 2H-tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 15.2 m/z 485 [MH]⁺ RT 2.96 min 596

8-chloro-1-{3-[5-(1- phenylcyclopropyl)- 2H-tetrazol-2- yl]propyl}-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 4.6 m/z 509 [MH]⁺ RT 3.00 min

Example 597 1-[5-(1,3-Benzoxazol-2-yl)pentyl]-8-chloro-3-ethyl-3,7-dihydro-1H-purine-2,6-dione a) 1-[5-(1,3-Benzoxazol-2-yl)pentyl]-8-chloro-3-ethyl-3,7-dihydro-1H-purine-2,6-dione

a) A solution of 3-ethyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.095 g, 0.37 mmol) in DMF (10 ml) was treated with potassium carbonate (0.0615 g, 0.45 mmol) and 2-(5-chloropentyl)-1,3-benzoxazole (0.091 g, 0.41 mmol) and the mixture heated at 70° C. for 4.5 h. The mixture was cooled and degassed by the repeated application of vacuum to the reaction mixture and subsequent backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol) and morpholine (0.32 ml, 3.7 mmol) and the mixture stirred for 4 h in a nitrogen atmosphere. The mixture was evaporated to dryness and the residue partitioned between 25 ml of ethyl acetate and 25 ml of brine. The aqueous phase was re-extracted with 25 ml of ethyl acetate and the combined organics dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 5 ml of methanol and added to a 5 g aminopropyl SPE which was subsequently washed with methanol and the product eluted with a 5% solution of acetic acid in methanol. Product-containing fractions were pooled and evaporated to reveal a colourless gum which was triturated with diethyl ether and dried to give the title compound as a white solid (0.0538 g, 36%).

LC/MS: m/z 402 [MH]⁺, RT 3.06 min

b) 2-(5-Chloropentyl)-1,3-benzoxazole

6-Chloro-N-(2-hydroxyphenyl)hexanamide (0.95 g, 3.9 mmol) was treated with toluene (20 ml) and 4-toluenesulfonic acid monohydrate (0.05 g, 0.26 mmol) and the mixture heated in the microwave at 160° C. for 1 h then cooled and evaporated. The residue was partition between 25 ml of ethyl acetate and 25 ml of saturates aqueous sodium bicarbonate. The aqueous phase was extracted twice more with 25 ml ethyl acetate and the combined organics dried over magnesium sulfate, filtered and evaporated to dryness. The product was then purified by flash chromatography (gradient elution: cyclohexane to cyclohexane/ethyl acetate 1:1) to give 2-(5-chloropentyl)-1,3-benzoxazole as a colourless oil which solidified upon standing (0.47 g, 53%).

LC/MS: m/z 224 [MH]⁺, RT 3.32 min

c) 6-chloro-N-(2-hydroxyphenyl)hexanamide

2-Aminophenol (0.5 g, 4.6 mmol) was stirred in ethyl acetate (15 ml) and treated dropwise with 6-chlorohexanoyl chloride (0.664 ml, 5.5 mmol) and then dropwise with triethylamine (0.95 ml, 6.9 mmol). After 1 h the mixture was washed with 2×25 ml of saturated aqueous sodium bicarbonate and the organic phase dried over magnesium sulfate, filtered and evaporated to dryness to give 6-chloro-N-(2-hydroxyphenyl)hexanamide as a pale brown solid (0.05 g, 86%).

LC/MS: m/z 242 [M]⁺, RT 2.95 min.

The following compounds (Table 33) were prepared using a method analogous to that for Example 597.

TABLE 33 Yield Example Structure Name (mg) LC/MS 598

1-[5-(1,3- benzoxazol-2- yl)pentyl]-8- chloro-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 60.5 m/z 416 [MH]⁺ RT 3.23 mins 599

1-[5-(1,3- benzoxazol-2- yl)pentyl]-3-butyl- 8-chloro-3,7- dihydro-1H- purine-2,6-dione 55.1 m/z 428 [MH]⁺ RT 3.42 mins 600

3-butyl-8-chloro-1- [5-(6-methyl-1,3- benzoxazol-2- yl)pentyl]-3,7- dihydro-1H- purine-2,6-dione 68.9 m/z 444 [MH]⁺ RT 3.56 mins

Example 601 1-[5-(1,3-Benzothiazol-2-yl)pentyl]-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione a) 1-[5-(1,3-Benzothiazol-2-yl)pentyl]-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.053 g, 0.19 mmol) in DMF (5 ml) was treated with potassium carbonate (0.026 g, 0.19 mmol) and 2-(5-chloropentyl)-1,3-benzothiazole (0.0498 g, 0.21 mmol) and the mixture heated at 60° C. for 3 days. The mixture was cooled and degassed by the repeated application of vacuum to the reaction mixture and subsequent backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.0294 g, 0.025 mmol) and morpholine (0.164 ml, 1.9 mmol) and the mixture stirred for 18 hours in a nitrogen atmosphere. The mixture was evaporated to dryness and the residue partitioned between 25 ml of ethyl acetate and 25 ml of saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 5 ml of methanol and added to a 5 g aminopropyl SPE which was subsequently washed with methanol and the product eluted with a 5% solution of acetic acid in methanol. Product-containing fractions were pooled and evaporated and the residue subjected to purification by MDAP to give the title compound as a white solid (0.0101 g, 12%).

LC/MS: m/z 446 [MH]⁺, RT 3.55 min.

b) 2-(5-Chloropentyl)-1,3-benzothiazole

An ice-cooled solution of 2-aminothiophenol (0.376 ml, 3.54 mmol) in anhydrous THF (5 ml) was treated with diisopropylethylamine (0.62 ml, 3.54 mmol) followed by 6-chlorohexanoyl chloride (0.36 ml, 2.95 mmol). The mixture was stirred at ambient temperature for 2 h then heated at reflux for 19 h and then cooled and diluted with DCM (10 ml). The solution was washed with 10 ml of 2M aqueous hydrochloric acid, 10 ml of 2M aqueous sodium hydroxide and 10 ml of brine; dried over magnesium sulfate, filtered and evaporated to reveal 0.4122 g of a pale yellow oil. The product was purified by flash chromatography using a gradient elution from cyclohexane to cyclohexane/ethyl acetate (7:3) to give 2-(5-chloropentyl)-1,3-benzothiazole as a colourless oil (0.0541 g, 6%).

LC/MS: m/z 240 [MH]⁺, RT 3.48 min.

Example 602 3-Butyl-8-chloro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (0.08 g, 0.19 mmol) in DMF (5 ml) was treated with potassium carbonate (0.08 g, 0.6 mmol) and 1-benzylpiperazine (0.04 g, 0.23 mmol) and then heated at 70° C. for 2 h. The mixture was cooled, evaporated to dryness and partitioned between 10 ml of DCM and 10 ml of water. The organic phase was evaporated to dryness and the residue dissolved in anhydrous THF (5 ml). The solution was cautiously degassed by the repeated application of vacuum to the reaction mixture and subsequent backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.009 mmol) and morpholine (0.200 ml, 2.3 mmol) and the mixture stirred for 2 h in a nitrogen atmosphere. The mixture was evaporated and the residue taken up in 5 ml of methanol and added to a 2 g aminopropyl SPE cartridge which was then washed with methanol and the product eluted using a 3% solution of acetic acid in methanol. Product-containing fractions were pooled and evaporated to dryness. The product was then purified by flash chromatography using a gradient elution from DCM/2% Acetic acid to DCM/20% MeOH/2% Acetic acid and the final product freeze-dried from 1,4-dioxan to give the title compound as a white solid (0.021 g, 24%).

LC/MS: m/z 459 [MH]⁺, RT 2.37 min.

The following compounds (Table 34) were prepared by the appropriate general methodology described above.

TABLE 34 Example Structure Name LC/MS 603

8-chloro-3-(2- cyclopropylethyl)-1-[2- (ethyloxy)ethyl]-3,7-dihydro- 1H-purine-2,6-dione m/z 327 [MH]⁺ RT 2.80 min 604

8-chloro-1-[2- (ethyloxy)ethyl]-3-(3- methylbutyl)-3,7-dihydro- 1H-purine-2,6-dione m/z 329 [MH]⁺ RT 3.02 min 605

4-{8-chloro-1-[2- ethyloxy)ethyl]-2,6-dioxo- 1,2,6,7-tetrahydro-3H-purin- 3-yl}butanenitrile m/z 326 [MH]⁺ RT 2.33 min 606

8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-m 1,2,4-oxadiazol-5-yl}propyl)- 3-[3-(1-piperidinyl)propyl]- 3,7-dihydro-1H-purine-2,6- dione m/z 548 [MH]⁺ RT 2.44 min 607

3-butyl-8-chloro-1-[2- (methyloxy)ethyl]-3,7- dihydro-1H-purine-2,6-dione m/z 301 [MH]⁺ RT 2.31 min 608

3-butyl-8-chloro-1-[3- (ethyloxy)propyl]-3,7- dihydro-1H-purine-2,6-dione m/z 329 [MH]⁺ RT 2.95 min 609

3-butyl-8-chloro-1-[3- (methyloxy)propyl]-3,7- dihydro-1H-purine-2,6-dione m/z 315 [MH]⁺ RT 2.36 min 610

3-butyl-8-chloro-1-[2- (ethyloxy)ethyl]-3,7-dihydro- 1H-purine-2,6-dione m/z 315 [MH]⁺ RT 2.34 min 611

3-butyl-8-chloro-1-[2- (propyloxy)ethyl]-3,7- dihydro-1H-purine-2,6-dione m/z 329 [MH]⁺ RT 2.71 min 612

methyl 4-(3-butyl-8-chloro- 2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1- yl)butanoate m/z 343 [MH]⁺ RT 2.56 min 613

methyl 5-(3-butyl-8-chloro- 2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1- yl)pentanoate m/z 357 [MH]⁺ RT 2.66 min 614

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)pentanamide m/z 342 [MH]⁺ RT 2.41 min 615

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N- (phenylmethyl)pentanamide m/z 432 [MH]⁺ RT 2.97 min 616

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)butanamide m/z 328 [MH]⁺ RT 2.34 min 617

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N- (phenylmethyl)butanamide m/z 418 [MH]⁺ RT 2.93 min 618

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N,N- dimethylpentanamide m/z 370 [MH]⁺ RT 2.26 min 619

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N- methylpentanamide m/z 356 [MH]⁺ RT 2.56 min 620

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N,N- dimethylbutanamide m/z 356 [MH]⁺ RT 2.59 min 621

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N- methylbutanamide m/z 342 [MH]⁺ RT 2.48 min 622

3-butyl-8-chloro-1-(4- morpholin-4-yl-4-oxobutyl)- 3,7-dihydro-1H-purine-2,6- dione m/z 398 [MH]⁺ RT 2.58 min 623

3-butyl-8-chloro-1-[3-(4- methyl-1,3-thiazol-5- yl)propyl]-3,7-dihydro-1H- purine-2,6-dione m/z 382 [MH]⁺ RT 3.00 min 624

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-[(4- chlorophenyl)methyl] pentanamide m/z 466 [MH]⁺ RT 3.26 min 625

8-chloro-1-{3-[4- (methyloxy)phenyl]propyl}- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 405 [MH]⁺ RT 3.65 min 626

8-chloro-1-[3-(4- cyclohexylphenyl)propyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 4.42 min 627

methyl 4-[3-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)propyl]benzoate m/z 433 [MH]⁺ RT 3.59 min 628

8-chloro-1-[3-(3,4- dichlorophenyl)propyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH]⁺ RT 4.03 min 629

8-chloro-3-pentyl-1-(4- phenylbutyl)-3,7-dihydro- 1H-purine-2,6-dione m/z 389 [MH]⁺ RT 3.87 min 630

ethyl 6-(8-chloro-2,6-dioxo- 3-pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)hexanoate m/z 399 [MH]⁺ RT 3.47 min 631

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- phenylpentanamide m/z 432 [MH]⁺ RT 3.36 min 632

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(2- phenylethyl)pentanamide m/z 460 [MH]⁺ RT 3.29 min 633

8-chloro-1-[5-(1,3-dihydro- 2H-isoindol-2-yl)-5- oxopentyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 458 [MH]⁺ RT 3.35 min 634

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(1H- imidazol-2- ylmethyl)pentanamide m/z 436 [MH]⁺ RT 2.32 min 635

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2- chlorophenyl)methyl] pentanamide m/z 480 [MH]⁺ RT 2.77 min 636

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3- chlorophenyl)methyl] pentanamide m/z 480 [MH]⁺ RT 3.42 min 637

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(1-methyl- 1H-imidazol-2- yl)methyl]pentanamide m/z 450 [MH]⁺ RT 2.32 min 638

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(pyridin-2- ylmethyl)pentanamide m/z 447 [MH]⁺ RT 2.70 min 639

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- (phenylmethyl)pentanamide m/z 460 [MH]⁺ RT 3.38 min 640

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(pyridin-4- ylmethyl)pentanamide m/z 447 [MH]⁺ RT 2.42 min 641

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(pyridin-3- ylmethyl)pentanamide m/z 447 [MH]⁺ RT 2.54 min 642

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3- (trifluoromethyl)phenyl] methyl}pentanamide m/z 514 [MH]⁺ RT 3.45 min 643

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[4- (trifluoromethyl)phenyl] methyl}pentanamide m/z 514 [MH]⁺ RT 3.47 min 644

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{(4- (methyloxy)phenyl]methyl} pentanamide m/z 476 [MH]⁺ RT 2.67 min 645

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(4- fluorophenyl)methyl] pentanamide m/z 464 [MH]⁺ RT 3.26 min 646

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3- (methyloxy)phenyl]methyl} pentanamide m/z 326 [MH]⁺ RT 3.21 min 647

5-(8-chloro-2,6-dioxo-3- pentyl-2,3.6,7-tetrahydro- 1H-purin-1-yl)-N-[(3,4- dichlorophenyl)methyl] pentanamide m/z 514 [MH]⁺ RT 3.56 min 648

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3- (methylsulfonyl)phenyl] methyl}pentanamide m/z 524 [MH]⁺ RT 2.97 min 649

5-(8-chloro-2,6-dioxo-3- pentyl-2.3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[6- (methyloxy)pyridin-3- yl]methyl}pentanamide m/z 477 [MH]⁺ RT 3.01 min 650

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3,4- difluorophenyl)methyl] pentanamide m/z 482 [MH]⁺ RT 3.33 min 651

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3- (dimethylamino)phenyl] methyl}pentanamide m/z 489 [MH]⁺ RT 3.01 min 652

N-(1-benzothien-2- ylmethyl)-5-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)pentanamide m/z 502 [MH]⁺ RT 3.48 min 653

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(3- thienylmethyl)pentanamide m/z 452 [MH]⁺ RT 3.18 min 654

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3- hydroxyphenyl)methyl] pentanamide m/z 462 [MH]⁺ RT 3.04 min 655

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3- fluorophenyl)methyl] pentanamide m/z 464 [MH]⁺ RT 3.28 min 656

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-({4- [(difluoromethyl)oxy]phenyl} methyl)pentanamide m/z 512 [MH]⁺ RT 3.34 min 657

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-({4- [(trifluoromethyl)oxy]phenyl} methyl)pentanamide m/z 530 [MH]⁺ RT 3.50 min 658

5-(8-chloro-2,6-dioxo-3- pentyl-2.3,6,7-tetrahydro- 1H-purin-1-yl)-N-(pyrazin-2- ylmethyl)pentanamide m/z 448 [MH]⁺ RT 2.74 min 659

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2,3 dichlorophenyl)methyl] pentanamide m/z 514 [MH]⁺ RT 3.55 min 660

N-(biphenyl-3-ylmethyl)-5- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)pentanamide m/z 522 [MH]⁺ RT 3.61 min 661

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(1- phenylethyl)pentanamide m/z 460 [MH]⁺ RT 3.30 min 662

N-[(3-aminophenyl)methyl]- 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)pentanamide m/z 461 [MH]⁺ RT 2.79 min 663

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(4- methylphenyl)methyl] pentanamide m/z 460 [MH]⁺ RT 3.36 min 664

N-(biphenyl-4-ylmethyl)-5- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)pentanamide m/z 522 [MH]⁺ RT 3.63 min 665

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- (naphthalen-1- ylmethyl)pentanamide m/z 496 [MH]⁺ RT 3.48 min 666

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- (naphthalen-2- ylmethyl)pentanamide m/z 496 [MH]⁺ RT 3.50 min 667

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3,5- dimethylphenyl)methyl] pentanamide m/z 474 [MH]⁺ RT 3.48 min 668

(3-methylphenyl)methyl 5- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)pentanoate m/z 461 [MH]⁺ RT 3.78 min 669

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- (phenylmethyl)pentanamide m/z 46 [MH]⁺ RT 3.12 min 670

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2- methylphenyl)methyl] pentanamide m/z 460 [MH]⁺ RT 3.22 min 671

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3,4- dimethylphenyl)methyl] pentanamide m/z 474 [MH]⁺ RT 3.34 min 672

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3- cyanophenyl)methyl] pentanamide m/z 471 [MH]⁺ RT 3.14 min 673

8-chloro-1-(2- hydroxypropyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 315 [MH]⁺ RT 2.73 min 674

8-chloro-1-(2-hydroxybutyl)- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 329 [MH]⁺ RT 2.91 min 675

N-[(3-bromophenyl)methyl]- 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)pentanamide m/z 524 [MH]⁺ RT 3.43 min 676

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- {[3- (trifluoromethyl)phenyl] methyl}pentanamide m/z 528 [MH]⁺ RT 3.55 min 677

1,1-dimethylethyl [2-(8- chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)ethyl]carbamate m/z 400 [MH]⁺ RT 3.21 min 678

1-(2-aminoethyl)-8-chloro-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 300 [MH]⁺ RT 2.14 min 679

8-chloro-1-(2-hydroxy-4- phenylbutyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 405 [MH]⁺ RT 3.43 min 680

8-chloro-1-(2-hydroxy-3- phenylpropyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 391 [MH]⁺ RT 3.17 min 681

N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)ethyl]acetamide m/z 342 [MH]⁺ RT 2.61 min 682

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-(2- phenylethyl)butanamide m/z 432 [MH]⁺ RT 3.06 min 683

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-[2-(3- methylphenyl)ethyl]butanamide m/z 446 [MH]⁺ RT 3.19 min 684

4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-[(3- methylphenyl)methyl]butanamide m/z 432 [MH]⁺ RT 3.14 min 685

8-chloro-1-(2-hydroxy-1- methylethyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 315 [MH]⁺ RT 2.80 min 686

2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- (2-phenylethyl)acetamide m/z 462 [MH]⁺ RT 3.23 min 687

2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- [(3- methylphenyl)methyl]acetamide m/z 462 [MH]⁺ RT 3.28 min 688

2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- [(4- methylphenyl)methyl]acetamide m/z 462 [MH]⁺ RT 3.27 min 689

2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,67-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- methyl-N- (phenylmethyl)acetamide m/z 462 [MH]⁺ RT 3.27 min 690

2-{(2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- {[3- (trifluoromethyl)phenyl]methyl} acetamide m/z 516 [MH]⁺ RT 3.39 min 691

2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- [2-(3- methylphenyl)ethyl]acetamide m/z 476 [MH]⁺ RT 3.36 min 692

2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]oxy}-N- methyl-N-{[3- (trifluoromethyl)phenyl]methyl} acetamide m/z 462 [MH]⁺ RT 3.27 min 693

N-[(3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)propyl]benzenesulfonamide m/z 454 [MH]⁺ RT 3.29 min 694

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3- phenylpropanamide m/z 446 [MH]⁺ RT 3.27 min 695

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-1- phenylmethanesulfonamide m/z 468 [MH]⁺ RT 3.29 min 696

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2- phenylacetamide m/z 432 [MH]⁺ RT 3.18 min 697

1-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3-[(3- methylphenyl)methyl]urea m/z 461 [MH]⁺ RT 3.29 min 698

1-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3-[(4- methylphenyl)methyl]urea m/z 461 [MH]⁺ RT 3.29 min 699

3-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-1- methyl-1-{[3- (trifluoromethyl)phenyl]methyl} urea m/z 529 [MH]⁺ RT 3.51 min 700

1-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3- (phenylmethyl)urea m/z 447 [MH]⁺ RT 3.17 min 701

2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl (phenylmethyl)carbamate m/z 434 [MH]⁺ RT 3.24 min 702

2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [(4- methylphenyl)methyl]carbamate m/z 448 [MH]⁺ RT 3.34 min 703

2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl (2- phenylethyl)carbamate m/z 448 [MH]⁺ RT 3.34 min 704

2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [2-(3- methylphenyl)ethyl]carbamate m/z 462 [MH]⁺ RT 3.48 min 705

2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [2-(4- methylphenyl)ethyl]carbamate m/z 462 [MH]⁺ RT 3.48 min 706

2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [(3- methylphenyl)methyl]carbamate m/z 448 [MH]⁺ RT 3.37 min 707

3-butyl-8-chloro-1-(2- hydroxyethyl)-3,7-dihydro- 1H-purine-2,6-dione m/z 287 [MH]⁺ RT 2.42 min 708

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(4- propylphenyl)pentanamide m/z 474 [MH]⁺ RT 3.73 min 709

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(2- ethylphenyl)pentanamide m/z 460 [MH]⁺ RT 3.41 min 710

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(3- ethylphenyl)pentanamide m/z 460 [MH]⁺ RT 3.58 min 711

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl [(4- fluorophenyl)methyl]carbamate m/z 466 [MH]⁺ RT 3.43 min 712

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl methyl(phenylmethyl)carbamate m/z 462 [MH]⁺ RT 3.54 min 713

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl [(4- methylphenyl)methyl]carbamate 714

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl [(2- methylphenyl)methyl]carbamate m/z 462 [MH]⁺ RT 3.50 min 715

(4-fluorophenyl)methyl [3-(8- chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 466 [MH]⁺ RT 3.36 min 716

3-thienylmethyl [3-(8-chloro- 2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)propyl]carbamate m/z 454 [MH]⁺ RT 3.27 min 717

(4-methylphenyl)methyl [3- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 462 [MH]⁺ RT 3.45 min 718

(2-methylphenyl)methyl [3- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 462 [MH]⁺ RT 3.42 min 719

2-(4-fluorophenyl)ethyl [3- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 480 [MH]⁺ RT 3.49 min 720

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl (2- phenylethyl)carbamate m/z 462 [MH]⁺ RT 3.50 min 721

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl propylcarbamate m/z 400 [MH]⁺ RT 3.20 min 722

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl (2- methyl-2- phenylpropyl)carbamate m/z 490 [MH]⁺ RT 3.66 min 723

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl (1- methyl-1- phenylethyl)carbamate m/z 476 [MH]⁺ RT 3.59 min 724

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(2-methyl- 2- phenylpropyl)pentanamide m/z 488 [MH]⁺ RT 3.53 min 725

5-(8-chloro-2,6-dioxo-3- pentyl-2,36,7-tetrahydro- 1H-purin-1-yl)-N-[(4- fluorophenyl)methyl]-N- methylpentanamide m/z 478 [MH]⁺ RT 3.46 min 726

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2- fluorophenyl)methyl]pentanamide m/z 464 [MH]⁺ RT 3.32 min 727

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2-(3- methylphenyl)acetamide m/z 446 [MH]⁺ RT 3.37 min 728

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2-(4- fluorophenyl)acetamide m/z 450 [MH]⁺ RT 3.28 min 729

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2-(4- methylphenyl)acetamide m/z 446 [MH]⁺ RT 3.36 min 730

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2- methyl-2- phenylpropanamide m/z 460 [MH]⁺ RT 3.50 min 731

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3- methyl-3-phenylbutanamide m/z 474 [MH]⁺ RT 3.51 min 732

N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3-(3- methylphenyl)propanamide m/z 460 [MH]⁺ RT 3.45 min 733

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(1- phenylcyclopropyl)pentanamide m/z 472 [MH]⁺ RT 3.29 min 734

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- phenylpentanamide m/z 446 [MH]⁺ RT 3.27 min 735

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(3- methylphenyl)pentanamide m/z 446 [MH]⁺ RT 3.41 min 736

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- (3- methylphenyl)pentanamide m/z 460 [MH]⁺ RT 3.41 min 737

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(4- methylphenyl)pentanamide m/z 446 [MH]⁺ RT 3.40 min 738

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- (cyclohexylmethyl)pentanamide m/z 452 [MH]⁺ RT 3.40 min 739

8-chloro-3-pentyl-1-[2- (phenylamino)ethyl]-3,7- dihydro-1H-purine-2,6-dione m/z 376 [MH]⁺ RT 3.55 min 740

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- (4- methylphenyl)pentanamide m/z 460 [MH]⁺ RT 3.41 min 741

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- cyclohexylpentanamide m/z 438 [MH]⁺ RT 3.25 min 742

N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)ethyl]benzenesulfonamide m/z 440 [MH]⁺ RT 3.08 min 743

N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]-1- phenylmethanesulfonamide m/z 454 [MH]⁺ RT 3.15 min 744

phenyl [2-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)ethyl]carbamate m/z 420 [MH]⁺ RT 3.18 min 745

phenylmethyl [2-(8-chloro- 2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)ethyl]carbamate m/z 434 [MH]⁺ RT 3.23 min 746

N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)ethyl]benzamide m/z 404 [MH]⁺ RT 3.04 min 747

N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]-2- phenylacetamide m/z 418 [MH]⁺ RT 2.99 min 748

N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]-3- phenylpropanamide m/z 432 [MH]⁺ RT 3.14 min 749

8-chloro-1-[(1- hydroxycyclopropyl)methyl]- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 327 [MH]⁺ RT 2.82 min 750

phenyl [3-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)propyl]carbamate m/z 434 [MH]⁺ RT 3.31 min 751

2-phenylethyl [3-(8-chloro- 2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)propyl]carbamate m/z 462 [MH]⁺ RT 3.48 min 752

2-pyridin-4-ylethyl [3-(8- chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 463 [MH]⁺ RT 2.44 min 753

2-pyridin-2-ylethyl [3-(8- chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 480 [MH]⁺ RT 2.44 min 754

2-(2-fluorophenyl)ethyl [3- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 480 [MH]⁺ RT 3.46 min 755

2-(1H-imidazol-1-yl)ethyl [3- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 452 [MH]⁺ RT 2.30 min 756

2-(1H-imidazol-2-yl)ethyl [3- (8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 452 [MH]⁺ RT 2.31 min 757

8-chloro-3-pentyl-1-{3-[5- (phenylmethyl)-1H-tetrazol- 1-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 3.32 min 758

8-chloro-1-[3-(1H-imidazol- 4-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 365 [MH]⁺ RT 2.27 min 759

8-chloro-3-pentyl-1-{3-[1- (phenylmethyl)-1H-imidazol- 4-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione m/z 455 [MH]⁺ RT 2.61 min 760

8-chloro-3-pentyl-1-[3-(3- thienyl)propyl]-3,7-dihydro- 1H-purine-2,6-dione m/z 381 [MH]⁺ RT 3.61 min 761

8-chloro-3-pentyl-1-[3-(2- thienyl)propyl]-3,7-dihydro- 1H-purine-2,6-dione m/z 381 [MH]⁺ RT 3.69 min 762

3-butyl-8-chloro-1-{3-[5- (phenylmethyl)-1H-1,2,4- triazol-1-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 442 [MH]⁺ RT 2.94 min 763

8-chloro-1-{3-[5- (phenylmethyl)-2H-tetrazol- 2-yl]propyl}-3-propyl-3,7- dihydro-1H-purine-2,6-dione m/z 429 [MH]⁺ RT 3.14 min 764

8-chloro-3-methyl-1-{3-[5- (phenylmethyl)-1,2,4- oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 401 [MH]⁺ RT 2.88 min 765

8-chloro-3-methyl-1-{3-[3- (phenylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 401 [MH]⁺ RT 2.89 min 766

8-chloro-3-ethyl-1-{3-[5- (phenylmethyl)-1,2,4- oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 415 [MH]⁺ RT 2.97 min 767

4-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)butanoic acid m/z 343 [MH]⁺ RT 2.81 min 768

8-chloro-3-pentyl-1-[3-(3-{[3- (trifluoromethyl)-1H-pyrazol- 1-yl]methyl}-1,2,4- oxadiazol- 5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione m/z 515 [MH]⁺ RT 3.43 min 769

8-chloro-1-{4-[3-(4- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 475 [MH]⁺ RT 3.71 min 770

8-chloro-3-pentyl-1-(4-{3-[4- (trifluoromethyl)phenyl]- 1,2,4-oxadiazol-5-yl}butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z 525 [MH]⁺ RT 3.92 min 771

8-chloro-1-(4-{3-[4- (dimethylamino)phenyl]- 1,2,4-oxadiazol-5-yl}butyl)- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 500 [MH]⁺ RT 3.73 min 772

8-chloro-1-{4-[3-(5-chloro-2- thienyl)-1 2,4-oxadiazol-5- yl]butyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 497 [MH]⁺ RT 3.88 min 773

8-chloro-3-pentyl-1-[3-(3- phenyl-1,2,4-oxadiazol-5- yl)propyl]-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH]⁺ RT 3.51 min 774

8-chloro-1-{4-[3-(3,4- dichlorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 525 [MH]⁺ RT 4.12 min 775

8-chloro-3-pentyl-1-{4-[3- (pyridin-3-ylmethyl)-1,2,4- oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 472 [MH]⁺ RT 2.90 min 776

8-chloro-3-pentyl-1-(2-{[(3- phenyl-1,2,4-oxadiazol-5- yl)methyl]oxy}ethyl)-3,7- dihydro-1H-purine-2,6-dione m/z 459 [MH]⁺ RT 3.45 min 777

8-chloro-3-pentyl-1-[3-(3-{[4- (trifluoromethyl)phenyl] methyl}-1,2,4-oxadiazol-5- yl)propyl]-3,7-dihydro-1H- purine-2,6-dione m/z 525 [MH]⁺ RT 3.69 min 778

8-chloro-1-(3-{3- [(pentafluorophenyl)methyl]- 1,2,4-oxadiazol-5-yl}propyl)- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 547 [MH]⁺ RT 3.66 min 779

1-{3-[3-(1-benzothien-2-yl)- 1,2,4-oxadiazol-5-yl]propyl}- 8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 499 [MH]⁺ RT 3.77 min 780

8-chloro-1-{3-[3-(2- methylphenyl)-1,2,4- oxadiazol-5-yl]propyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 3.62 min 781

8-chloro-1-(2,3- dihydroxypropyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z 331 [MH]⁺ RT 2.48 min 782

1-(4-biphenyl-4-ylbutyl)-8- chloro-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione m/z 465 [MH]⁺ RT 4.18 min 783

8-chloro-1-{3-[3- (phenylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 387 [MH]⁺ RT 2.63 min 784

8-chloro-1-{3-[5- (phenylmethyl)-1,2,4- oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 387 [MH]⁺ RT 2.65 min 785

8-chloro-3-pentyl-1-{4-[5- (1H-tetrazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 449 [MH]⁺ RT 4.03 min 786

3-butyl-8-chloro-1-{3-[5- (phenylmethyl)-1H-tetrazol- 1-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH]⁺ RT 3.11 min 787

8-chloro-1-{4-[5-(2- hydroxyphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 473 [MH]⁺ RT 3.84 min 788

8-chloro-1-{4-[5-(3-chloro-4- hydroxyphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 507 [MH]⁺ RT 3.74 min 789

1-[3-(1-benzofuran-2- yl)propyl]-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z 415 [MH]⁺ RT 5.10 min 790

1-[4-(1-benzofuran-2- yl)butyl]-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z 429 [MH]⁺ RT 3.88 min 791

8-chloro-1-{4-[5-(5- chloropyridin-2-yl)-1,2,4- oxadiazol-3-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione m/z 464 [MH]⁺ RT 3.30 min 792

8-chloro-1-{4-(5-(2,4- difluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione m/z 465 [MH]⁺ RT 3.48 min 793

8-chloro-1-{4-[5-(3- hydroxypropyl)-1,2,4- oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 439 [MH]⁺ RT 2.93 min 794

3-[4-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)butyl]benzonitrile m/z 414 [MH]⁺ RT 3.62 min 795

8-chloro-1-[4-(3- hydroxyphenyl)butyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 405 [MH]⁺ RT 3.48 min 796

1-{4-[6,7- bis(methyloxy)naphthalen-1- yl]butyl}-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z 499 [MH]⁺ RT 3.78 min 797

1-[4-(4-aminophenyl)butyl]- 8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 404 [MH]⁺ RT 3.02 min 798

8-chloro-1-[4-(3-hydroxy- 2,4,6-trimethylphenyl)butyl]- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 447 [MH]⁺ RT 3.78 min 799

8-chloro-1-[4-(2,6- dichlorophenyl)butyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 4.10 min 800

8-chloro-1-{4-[3- (methylsulfonyl)phenyl]butyl}- 3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 467 [MH]⁺ RT 3.33 min 801

8-chloro-1-{4-[3- (cyclopentylsulfonyl)phenyl] butyl}-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione m/z 521 [MH]⁺ RT 3.65 min 802

4-[4-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)butyl]benzonitrile m/z 414 [MH]⁺ RT 3.61 min 803

8-chloro-1-(4-naphthalen-1- ylbutyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 439 [MH]⁺ RT 4.00 min 804

8-chloro-3-pentyl-1-(4-{4- [(phenylmethyl)oxy]phenyl} butyl)-3,7-dihydro-1H-purine- 2,6-dione m/z 495 [MH]⁺ RT 4.06 min 805

8-chloro-1-[4-(4- fluorophenyl)butyl]-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z 407 [MH]⁺ RT 3.78 min 806

N-[4-{[4-(8-chloro-2,6-dioxo- 3-pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)butyl]oxy}-3- (methyloxy)phenyl]acetamide m/z 492 [MH]⁺ RT 3.09 min 807

3-butyl-8-chloro-1-[4-(5- phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH]⁺ RT 3.49 min 808

1-(4-biphenyl-3-ylbutyl)-8- chloro-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione m/z 465 [MH]⁺ RT 4.13 min 809

3-butyl-8-chloro-1-(4-{5-[2- fluoro-4- (trifluoromethyl)phenyl]- 1,2,4-oxadiazol-3-yl}butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z 529 [MH]⁺ RT 3.71 min 810

3-butyl-8-chloro-1-{4-[5-(4- chloro-2-fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 495 [MH]⁺ RT 3.64 min 811

3-butyl-8-chloro-1-{4-[5-(2,4- difluorophenyl)-1,2,4- oxadiazol-3-yl]butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 479 [MH]⁺ RT 3.49 min 812

3-butyl-8-chloro-1-{4-[5-(2,3- difluorophenyl)-1,2,4- oxadiazol-3-yl]butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 479 [MH]⁺ RT 3.53 min 813

3-butyl-8-chloro-1-{4-[5-(2- fluoro-4-methylphenyl)- 1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z 475 [MH]⁺ RT 3.51 min 814

3-butyl-8-chloro-1-(4- hydroxybutyl)-3,7-dihydro- 1H-purine-2,6-dione m/z 315 [MH]⁺ RT 2.54 min 815

3-butyl-8-chloro-1-{4-[5-(2,5- difluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 479 [MH]⁺ RT 3.50 min 816

3-butyl-8-chloro-1-{4-[5-(3,5- dichlorophenyl)-2H-tetrazol- 2-yl]butyl)-3,7-dihydro-1H- purine-2,6-dione m/z 511 [MH]⁺ RT 3.92 min 817

3-butyl-8-chloro-1-{4-[5-(6- methylpyridin-2-yl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 458 [MH]⁺ RT 3.12 min 818

3-butyl-8-chloro-1-(4-{5-]2- fluoro-5-(methyloxy)phenyl]- 1,2,4-oxadiazol-3-yl}butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z 491 [MH]⁺ RT 3.51 min 819

3-butyl-8-chloro-1-{4-(2,4- dioxo-5-(phenylmethyl)-1,3- thiazolidin-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 504 [MH]⁺ RT 3.36 min 820

3-butyl-8-butyl-1-[4-(3,5- dioxo1-phenyl-1,2,4- triazolidin-4-yl)-butyl]-3,7- dihydro-1H-purine-2,6-dione m/z 474 [MH]⁺ RT 2.91 min 821

3-butyl-8-chloro-1-{4-[5-(6- oxo-1,6-dihydropyridin-2-yl)- 1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z 460 [MH]⁺ RT 2.86 min 822

3-butyl-8-chloro-1-{4-[5-(6- fluoropyridin-2-yl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 462 [MH]⁺ RT 3.23 min 823

3-butyl-8-chloro-1-{4-[5-(3- chloro-2-fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 495 [MH]⁺ RT 3.69 min 824

3-butyl-8-chloro-1-{4-[5-(3- methylphenyl-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 457 [MH]⁺ RT 3.67 min 825

3-butyl-8-chloro-1-{4-[5-(3,5- dichloro-4-hydroxyphenyl)- 1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z 527 [MH]⁺ RT 3.92 min 826

3-butyl-8-chloro-1-(4-{5-[4- hydroxy-3- (methyloxy)phenyl]-1,2,4- oxadiazol-3-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 489 [MH]⁺ RT 3.27 min 827

3-butyl-8-chloro-1-{4-[5-(3- chloro-4-hydroxyphenyl)- 1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z 493 [MH]⁺ RT 3.61 min 828

3-butyl-8-chloro-1-{4-[5-(1H- indol-6-yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 482 [MH]⁺ RT 3.55 min 829

3-butyl-8-chloro-1-{4-(5-(2- methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 457 [MH]⁺ RT 3.67 min 830

3-butyl-8-chloro-1-(4-{-5[4- (methyloxy)phenyl]-1,2,4- oxadiazol-3-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473 [MH]⁺ RT 3.51 min 831

3-butyl-8-chloro-1-{4-[5-(4- fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 461 [MH]⁺ RT 3.54 min 832

3-butyl-8-chloro-1-[4-(5- pyrazin-2-yl-1,2,4-oxadiazol- 3-yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 445 [MH]⁺ RT 2.96 min 833

3-butyl-8-chloro-1-{4-[5-(6- oxo-1,6-dihydropyridin-3-yl)- 1,2,4-oxadiazol-3-yl]butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z 460 [MH]⁺ RT 2.78 min 834

1-{4-[5-(1H-benzimidazol-2- yl)-1,2,4-oxadiazol-3- yl]butyl}-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6- dione m/z 483 [MH]⁺ RT 3.22 min 835

3-butyl-8-chloro-1-{4-[5-(3- fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 461 [MH]⁺ RT 3.58 min 836

3-butyl-8-chloro-1-[4-(5- pyrimidin-2-yl-1,2,4- oxadiazol-3-yl)butyl]-3,7- dihydro-1H-purine-2,6-dione m/z 445 [MH]⁺ RT 2.84 min

Example 837 3-Butyl-8-chloro-1-{4-[5-(2-fluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-1-{4-[5-(2-fluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione

CDI (45 mg, 0.28 mmol) in anhydrous DMSO (0.5 ml) was added to 2-fluoro-4-hydroxybenzoic acid (40 mg, 0.25 mmol) and stirred at rt for 2 h. 5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) in DMSO (0.4 ml) was added and the resulting mixture heated at 90° C. for 18 h. Purification by MDAP afforded the title compound as a solid (38 mg, 28%).

LC/MS: m/z 477 [MH]⁺, RT 3.39 min.

¹H NMR (DMSO-d₆) δ: 0.87 (t, 3H, J=7 Hz), 1.27 (m, 2H), 1.56-1.78 (m, 6H), 2.77 (t, 2H, J=7 Hz), 3.90 (m, 4H), 6.80 (m, 2H), 7.91 (t, 1H, J=9 Hz), 11.01 (s, 1H), 14.45 (br s, 1H).

b) 5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide

5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile (8.5 g, 26 mmol) was dissolved in EtOH (100 ml). Hydroxylamine (50% in water; 2.6 ml, 39 mmol) was added and the mixture heated at 80° C. for 48 h under nitrogen. The reaction mixture was concentrated in vacuo, the resultant solid washed with methanol and dried to give the title compound as a solid (5.9 g, 47%).

LC/MS: m/z 357 [MH]⁺, RT 2.17 min.

c) 5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile

5-Bromopentanenitrile (4.54 ml, 39 mmol) and cesium carbonate (12.7 g) were added to a solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 35 mmol) in DMF (100 ml) and the mixture stirred under nitrogen at 40° C. overnight and allowed to cool.

The mixture was then degassed by the repeated successive application of a vacuum and then nitrogen pressure. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (2.86 g, 2.5 mmol) and morpholine (30.8 ml, 350 mmol). The mixture was stirred in a nitrogen atmosphere for 3 h and then partitioned between EtOAc and 2M aqueous hydrochloric acid. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phases were concentrated in vacuo to give a solid that was washed with ether, filtered and dried. The filtrate was concentrated and purified on an aminopropyl column eluting with MeOH followed by 3% AcOH/MeOH. The product-containing fractions were combined and concentrated to give a solid, which was combined with the filtered product. The title compound was obtained as a solid (10.5 g, 93%).

LC/MS: m/z 324 [MH]⁺, RT 2.75 min.

The following compounds (Table 35) were prepared using a method analogous to that for Example 837, using the appropriate carboxylic acid.

844

3-butyl-8-chloro-1-[4-(5- isoquinolin-1-yl-1,2,4- oxadiazol-3-yl)butyl]-3,7- dihydro-1H-purine-2,6-dione m/z 494 [MH]⁺ RT 3.49 min 845

3-butyl-8-chloro-1-[4-(2-oxo- 3-phenylimidazolidin-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 459 [MH]⁺ RT 3.23 min 846

3-butyl-8-chloro-1-[4-(2,5- dioxo-3-phenylimidazolidin- 1-yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 473 [MH]⁺ RT 3.19 min 847

3-butyl-8-chloro-1-[4-(2-oxo- 3-phenylpyrrolidin-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 458 [MH]⁺ RT 3.12 min 848

N-[4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)butyl]-N- methylbenzenesulfonamide m/z 468 [MH]⁺ RT 3.28 min 849

3-butyl-8-chloro-1-[4-(4- phenyl-1H-imidazol-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 441 [MH]⁺ RT 2.60 min 850

3-butyl-8-chloro-1-[4-(2,5- dioxo-3-phenylpyrrolidin-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 472 [MH]⁺ RT 3.20 min 851

3-butyl-8-chloro-1-[4-(4- phenylpiperidin-1-yl)butyl]- 3,7-dihydro-1H-purine-2,6- dione m/z 458 [MH]⁺ RT 2.56 min 852

3-butyl-8-chloro-1-[4-(4- phenylpiperazin-1-yl)butyl]- 3,7-dihydro-1H-purine-2,6- dione m/z 459 [MH]⁺ RT 2.49 min 853

3-butyl-8-chloro-1-(4- mopholin-4-ylbutyl)-3,7- dihydro-1H-purine-2,6-dione m/z 384 [MH]⁺ RT 2.11 min 854

3-butyl-8-chloro-1-[4-(3,4- dihydroisoquinolin-2(1H)- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 430 [MH]⁺ RT 2.40 min 855

3-butyl-8-chloro-1-[4-(1,3- dihydro-2H-isoindol-2- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 416 [MH]⁺ RT 2.33 min 856

3-butyl-8-chloro-1-(4-{5-[2- fluoro-6-(methyloxy)phenyl]- 1,2,4-oxadiazol-3-yl}butyl]- 3,7-dihydro-1H-purine-2,6- dione m/z 491 [MH]⁺ RT 3.33 min 857

3-butyl-8-chloro-1-{4-[5-(2- cyclohexylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 525 [MH]⁺ RT 4.18 min 858

3-butyl-8-chloro-1-[4-(5- phenyl-1,3-oxazol-2- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 442 [MH]⁺ RT 3.46 min 859

3-butyl-8-chloro-1-[4-(4- phenyl-1,3-oxazol-2- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 442 [MH]⁺ RT 3.48 min 860

3-butyl-8-chloro-1-[4-oxo-4- (3-phenylpyrrolidin-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 458 [MH]⁺ RT 3.16 min 861

3-butyl-8-chloro-1-{4-[3-(2- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 461 [MH]⁺ RT 3.45 min 862

3-butyl-8-chloro-1-{4-[5-(4- fluorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 461 [MH]⁺ RT 3.47 min 863

3-butyl-8-chloro-1-{4-[5-(2,6- difluorophenyl)-2H-tetrazol- 2-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 479 [MH]⁺ RT 3.32 min 864

3-butyl-8-chloro-1-[4-(5- pyridin-2-yl-1H-tetrazol-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 444 [MH]⁺ RT 2.94 min 865

3-butyl-8-chloro-1-[4-(5- pyridin-2-yl-2H-tetrazol-2- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 444 [MH]⁺ RT 3.07 min 866

3-butyl-8-chloro-1-{4-[5-(2- methylphenyl)-2H-tetrazol- 2-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 3.54 min 867

3-butyl-8-chloro-1-{4-[5-(3- methylphenyl)-2H-tetrazol- 2-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 3.56 min 868

3-butyl-8-chloro-1-{4-[5-(2- chlorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 477 [MH]⁺ RT 3.68 min 869

3-butyl-8-chloro-1-(4-{5-[4- (methyloxy)phenyl]-2H- tetrazol-2-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473 [MH]⁺ RT 3.40 min 870

3-butyl-8-chloro-1-{4-[5-(4- chlorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 477 [MH]⁺ RT 3.68 min 871

3-butyl-8-chloro-1-{4-[5-(3- fluorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 461 [MH]⁺ RT 3.51 min 872

3-butyl-8-chloro-1-{4-[5-(2- fluorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 461 [MH]⁺ RT 3.34 min 873

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)pentanoic acid m/z 343 [MH]⁺ RT 2.76 min 874

5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)pentanoic acid m/z 315 [MH]⁺ RT 2.74 min 875

3-butyl-8-chloro-1-[4-(3- phenyl-1-pyrrolidinyl)butyl]- 3,7-dihydro-1H-purine-2,6- dione m/z 444 [MH]⁺ RT 2.51 min 876

3-butyl-8-chloro-1-{4-[5-(2- methylphenyl)-1H-tetrazol- 1-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH]⁺ RT 3.16 min 877

3-butyl-8-chloro-1-[4-(5- phenyl-1H-tetrazol-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH]⁺ RT 3.08 min 878

3-butyl-8-chloro-1-(4-{5-[4- (methyloxy)phenyl]-1H- tetrazol-1-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473 [MH]⁺ RT 3.10 min 879

3-butyl-8-chloro-1-(4-{5-[3- (methyloxy)phenyl]-2H- tetrazol-2-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473 [MH]⁺ RT 3.40 min 880

8-chloro-3-ethyl-1-(3-{(5Z)- 5-[(4- fluorophenyl)methylidene]- 2,4-dioxo-1,3-thiazolidin-3- yl}propyl)-3,7-dihydro-1H- purine-2,6-dione m/z 478 [MH]⁺ RT 3.31 min 881

3-butyl-8-chloro-1-(3-{(5Z)- 5-[(4- fluorophenyl)methylidene]- 2,4-dioxo-1,3-thiazolidin-3- yl}propyl)-3,7-dihydro-1H- purine-2,6-dione m/z 506 [MH]⁺ RT 3.63 min 882

8-chloro-1-[4-(3-phenyl- 1,2,4-oxadiazol-5-yl)butyl]- 3-(2-propen-1-yl)-3,7- dihydro-1H-purine-2,6-dione m/z 427 [MH]⁺ RT 3.20 min 883

8-chloro-3- (cyclopropylmethyl)-1-[4-(5- phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 441 [MH]⁺ RT 3.38 min 884

8-chloro-3- (cyclobutylmethyl)-1-[4-(5- phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 455 [MH]⁺ RT 3.53 min 885

8-chloro-1-[4-(5-phenyl- 1,2,4-oxadiazol-3-yl)butyl]- 3-(4,4,4-trifluorobutyl)-3,7- dihydro-1H-purine-2,6-dione m/z 497 [MH]⁺ RT 3.46 min 886

8-chloro-3-(4-fluorobutyl)-1- [4-(5-phenyl-1,2,4- oxadiazol-3-yl)butyl]-3,7- dihydro-1H-purine-2,6-dione m/z 461 [MH]⁺ RT 3.26 min 887

8-chloro-3-[2- (ethyloxy)ethyl]-1-[4-(5- phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 459 [MH]⁺ RT 3.16 min 888

8-chloro-3-(2-methylpropyl)- 1-[4-(5-phenyl-1,2,4- oxadiazol-3-yl)butyl]-3,7- dihydro-1H-purine-2,6-dione m/z 443 [MH]⁺ RT 3.44 min 889

8-chloro-3-(3- cyclopropylpropyl)-1-[4-(5- phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 469 [MH]⁺ RT 3.63 min 890

8-chloro-3-methyl-1-[4-(5- phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 401 [MH]⁺ RT 2.98 min 891

3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl[(2- fluorophenyl)methyl]carbamate m/z 466 [MH]⁺ RT 3.44 min 892

methyl 6-{3-[4-(3-butyl-8- chloro-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1- yl)butyl]-1,2,4-oxadiazol-5- yl}-3-pyridinecarboxylate m/z 502 [MH]⁺ RT 3.22 min 893

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(3- hydroxypropyl)-N- (phenylmethyl)pentanamide m/z 504 [MH]⁺ RT 2.64 min 894

5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(2- hydroxyethyl)-N- (phenylmethyl)pentanamide m/z 490 [MH]⁺ RT 3.13 min

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. 

1-19. (canceled)
 20. A compound of formula (I):

and pharmaceutically acceptable derivatives thereof, wherein: R¹ represents -(alkylene)_(m)-X-(alkylene)_(n)-Y; wherein X represents A, A1, A2 or a direct link; wherein: A represents a group selected from cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, and —CH₂—OC(O)—; A1 represents a group selected from —CH₂—O—(CH₂)_(q)aryl-O—, —CH₂—O—(CH₂)_(w)N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)O—, —CH₂—N(R⁵)C(O)—, —CH₂—(O)_(p)—(CH₂)_(q)C(O)NR⁵—, —CH₂—N(R⁵)C(O)N(R⁵)—, —CH₂—C(O)N((CH₂)_(w)OH)—, —CH₂—NR⁵—S(O)₂—, CH₂—S(O)₂NR⁵—, —CH₂—C(O)O—, —O—, —NR⁵—, and —S—; and A2 represents —CH(OH)—; R² is selected from hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of a group independently selected from: C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁₋₆ haloalkyl, halogen, —CN, —OR⁴, —(CH₂)_(n)COR⁴, —C(O)OR⁴, —OCOR⁴, —(CH₂)_(n)NR⁵R⁶, —(NH)_(p)CONR⁵R⁶, —OCONR⁵R⁷, and —NR⁵C(O)OR⁷; R³ represents a group selected from halogen and CN; wherein: R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n) cycloalkyl, —(CH₂)_(n) cycloalkenyl, —(CH₂)_(n) heterocyclyl, —(CH₂)_(n) aryl, and —(CH₂)_(n) heteroaryl; R⁵ and R⁶ are independently selected from hydrogen and C₁₋₄ alkyl; R⁷ represents a group selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(t) cycloalkyl, —(CH₂)_(n)cycloalkenyl, —(CH₂)_(t) heterocyclyl, —(CH₂)_(t) aryl, and —(CH₂)_(t) heteroaryl; R⁸ represents a group selected from C₁₋₄ alkyl; R⁹ represents a group selected from C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n) cycloalkyl, —(CH₂)_(n)cycloalkenyl, —(CH₂)_(n)heterocyclyl, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, and CN; m represents an integer selected from 1, 2, 3, 4 and 5; n represents an integer selected from 0, 1, 2, 3, 4 and 5; p represents an integer selected from 0 and 1; q represents an integer selected from 0, 1 and 2; t represents an integer selected from 1 and 2; w represents an integer selected from 2, 3 and 4; and provided that: when X is A, A1 or A2, Y is a group selected from heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, —NH-aryl, —O(CH₂)_(n)-aryl, —O-heteroaryl, —OR⁵, —C(O)OR⁵, —C(O)O—C₆ aryl, —OC(O)R⁴, —CH(aryl)₂, —CH(heteroaryl)₂, and —C₁₋₆ haloalkyl; when X is A1 and Y is selected from —O(CH₂)_(n)-aryl, —O-heteroaryl, —OR⁵, —OC(O)R⁴, or —NH-aryl, and n is an integer selected from 2, 3, 4 and 5; when X is A1 and Y is —C₁₋₆ haloalkyl; when X is A2, n is an integer selected from 1, 2, 3, 4 and 5; when X is a direct link, (m+n) is an integer selected from 2 to 10; when X is a direct link and (m+n) is an integer selected from 3 to 10, Y represents a group selected from —C(O)(CH₂)_(q)OR⁴, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocyclyl, heteroaryl, heterocyclyl, Aryl, 3 or 4 ring fused system, —CH(aryl)₂, —CH(heteroaryl)₂, —OR⁵, —NR⁵R⁶, —NR⁵C(O)OR⁷, —(O)_(p)C(O)NR⁵R⁷, and —NR⁵C(O)R⁷; when X is a direct link and (m+n) is 2, Y represents a group selected from —OR⁵, —NH₂, and —NR⁵C(O)OR⁸; when Y incorporates a ring, that ring may be optionally substituted by one or more of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, —(CH₂)_(q)NR⁵R⁷, —(CH₂)_(q)—(O)_(p)—(CH₂)_(q)—N(R⁵)C(O)OR⁸, —(CH₂)_(q)—N(R⁵)C(O)R⁸, —(CH₂)_(q)—(O)_(p)—(CH₂)_(q)—C(O)NR⁵R⁶, —(CH₂)_(q)—N(R⁵)C(O)N(R⁵)R⁶, —(CH₂)_(q)—C(O)N((CH₂)_(m)OH)R⁵, —(CH₂)_(q)—N(R⁵)—S(O)₂R⁸, —CH₂—S(O)₂N(R⁵)R⁶, —C₁₋₆ haloalkyl, —OCF₃, —OCH(F)₂, —OCH₂F, —C(O)OR⁵, —OR⁵, —R⁸CN, —CN, —SO₂R⁹, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)heterocycyl, —(CH₂)_(n)cycloalkyl, —(CH₂)_(n)cycloalkenyl, and —(CH₂)_(n)aryl; and when X is A1, A1 is —O— and Y is a ring which is substituted by aryl or heteroaryl, then m is an integer selected from 3, 4 and
 5. 21. A compound according to claim 20, wherein X is selected from A and A1.
 22. A compound according to claim 20, wherein R² is selected from C₃₋₆ alkyl.
 23. A compound according to claim 20, wherein X is selected from A and A1; wherein: A represents a group selected from heteroaryl and heterocyclyl, and A1 represents a group selected from CH₂—O—(CH₂)_(w)N(R⁵)C(O)O—, CH₂—N(R⁵)C(O)O—, CH₂—N(R⁵)C(O)—, CH₂—(O)_(p)—(CH₂)_(g)C(O)NR⁵—, CH₂—N(R⁵)C(O)N(R⁵)—, CH₂—C(O)N((CH₂)_(m)OH)—, CH₂—NR⁵—S(O)₂—, CH₂—S(O)₂NR⁵—, and CH₂—C(O)O—.
 24. A compound according to claim 23, wherein X represents A and A is heteroaryl.
 25. A compound according to claim 24, wherein A is a heteroaryl comprising a nitrogen heteroatom.
 26. A compound according to claim 20, wherein Y is selected from aryl, heteroaryl and O-aryl.
 27. A compound according to claim 20, wherein R³ is halogen.
 28. A compound according to claim 20, wherein R³ is chlorine.
 29. A method for treatment of disorders of lipid metabolism, which comprises administering a compound of formula (I) of claim
 20. 30. A method according to claim 29, wherein disorders of lipid metabolism are selected from diabetic dyslipidaemia, mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease, atherosclerosis, arteriosclerosis, hypertriglyceridaemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease or stroke.
 31. A method according to claim 30, wherein disorders of lipid metabolism are selected from diabetic dyslipidaemia, mixed dyslipidaemia, hypercholesteraemia, hypertriglyceridaemia, or hyperlipidaemia.
 32. A method according to claim 30, wherein the cardiovascular disease is selected from heart failure, atherosclerosis and arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease or stroke.
 33. A method for treatment of dyslipidaemia and hyperlipoproteinaemia, which comprises administering a compound of formula (I) of claim
 20. 34. A method for treatment of inflammatory diseases or conditions, which comprises administering a compound of formula (I) of claim
 20. 35. A method for treatment of a human or animal subject having a condition where under-activation of HM74A receptor contributes to the condition in which activation of the receptor is agonistic, which comprises administering an effective amount of a compound of formula (I) according to claim
 20. 36. A pharmaceutical formulation, which comprises at least one chemical entity according to claim 20 and at least one pharmaceutically acceptable diluent, excipient or carrier.
 37. A combination for administration together or separately, sequentially or simultaneously in separate or combined pharmaceutical formulations, which comprises at least one chemical entity according to claim 20 together with another therapeutically active agent.
 38. A pharmaceutical formulation, which comprises: (i) at least one chemical entity according to claim 20; (ii) one or more therapeutically active agent selected from statins, fibrates, bile-acid binding resins and nicotinic acid; and (iii) one or more pharmaceutically acceptable diluents, excipients or carriers. 